Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

Milademetan is a small‐molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P‐glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug‐drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan ({"type":"clinical-trial","attrs":{"text":"NCT03614455","term_id":"NCT03614455"}}NCT03614455) showed that concomitant administration of single‐dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC_inf) by 2.15‐fold (90% confidence interval [CI], 1.98–2.34) and 2.49‐fold (90% CI, 2.26–2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically‐based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A‐mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72‐fold (90% CI, 1.69–1.76) with fluconazole, 1.91‐fold (90% CI, 1.83–1.99) with erythromycin, and 2.02‐fold (90% CI, 1.93–2.11) with verapamil. In addition, it estimated that milademetan’s original dose (160 mg once daily) could be resumed from its half‐reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Milademetan is a CYP3A and P‐gp substrate and moderate CYP3A inhibitor. Evaluation of drug‐drug interaction (DDI) risk of milademetan by combining clinical studies and physiologically‐based pharmacokinetic (PBPK) modeling has not previously been described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Will milademetan PK be affected by the concomitant administration of strong or moderate CYP3A inhibitors? When can the original dose of milademetan be resumed after the discontinuation of strong CYP3A inhibitors?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study illustrates the use of a clinical DDI study and PBPK modeling in the early clinical development of milademetan to assess DDI risks in scenarios that have not yet been tested clinically at the time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

PBPK modeling integrates in vitro and clinical data to facilitate the mechanistic understanding of PKs. Recommendations from PBPK modeling can support the design of clinical studies for the investigation of DDIs.     

Effect of enzalutamide on PK of P‐gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters

Drug‐drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P‐glycoprotein [P‐gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration‐resistant prostate cancer (mCRPC). This was a phase I, open‐label, fixed‐sequence, crossover study ({"type":"clinical-trial","attrs":{"text":"NCT04094519","term_id":"NCT04094519"}}NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo‐to‐match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C_max), area under the concentration‐time curve from the time of dosing to the last measurable concentration (AUC_last), and AUC from the time of dosing extrapolated to time infinity (AUC_inf). Secondary end points were enzalutamide and N‐desmethyl enzalutamide (metabolite) plasma C_max, AUC during a dosing interval, where tau is the length of the dosing interval (AUC_tau), and concentration immediately prior to dosing at multiple dosing (C_trough). When administered with enzalutamide, there was a 17% increase in C_max, 29% increase in AUC_last, and 33% increase in AUC_inf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a “mild” inhibitor of P‐gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N‐desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter‐mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P‐gp and BCRP does not require dose adjustment in this patient population.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Enzalutamide is strong inducer of CYP3A4. Preclinical data have demonstrated that enzalutamide and its active metabolite, N‐desmethyl enzalutamide, have the potential to inhibit the efflux transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP).

• WHAT QUESTION DID THIS STUDY ADDRESS?

This clinical study evaluated the net inhibition and induction effect of enzalutamide on the pharmacokinetics (PK) of a transporter probe cocktail containing the P‐gp and BCRP substrates, digoxin and rosuvastatin, in men with metastatic castration‐resistant prostate cancer.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Concomitant administration with enzalutamide resulted in an increase in digoxin exposure, suggesting that enzalutamide is a “mild” inhibitor of P‐gp. No PK interaction was observed between enzalutamide and rosuvastatin, suggesting that enzalutamide has “no effect” on BCRP.

• HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Induction of CYP3A4 does not necessarily correlate with clinical effect on P‐gp and BCRP transporters. These findings are beneficial to guide future treatment recommendations, whereby concomitant administration of enzalutamide with medications that are P‐gp and BCRP substrates does not require dose adjustment.     

Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

The accurate prediction of OATP1B‐mediated drug–drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically‐based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP‐I) by CysA. In vivo K_i of unbound CysA for OATP1B (K_i,OATP1B), and the overall intrinsic hepatic clearance per body weight of CP‐I (CL_int,all,unit) were optimized to account for the CP‐I data (K_i,OATP1B, 0.536 ± 0.041 nM; CL_int,all,unit, 41.9 ± 4.3 L/h/kg). DDI simulation using K_i,OATP1B reproduced the dose‐dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro K_i,OATP1B failed. The Cluster Gauss–Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP‐I (β, CL_{int, all}, F_aF_g, R_dif, f_bile, f_syn, and v _syn), and K_i,OATP1B and K_i,MRP2 of CysA. Based on the accepted 546 parameter sets, the range of CL_{int, all} and K_i,OATP1B was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP‐I is a promising translational approach to predict OATP1B‐mediated DDIs in drug development.

Abbreviations

AUC

area under the concentration time curve

AUCR

area under the concentration time curve ratio (rifampicin/control)

BCRP

breast cancer resistance protein

CGNM

Cluster Gauss–Newton method

C_max

maximum concentration

CV

coefficient of variation

CysA

cyclosporin A

DDI

drug–drug interaction

K_i

inhibition constant

MRP2

multidrug resistance protein 2

OATP1B1

organic anion transporting polypeptide 1B1

OATP1B3

organic anion transporting polypeptide 1B3

PBPK

physiologically‐based pharmacokinetic

T_max

time to maximum concentration

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Physiologically‐based pharmacokinetic (PBPK) models are used to predict transporter‐mediated drug–drug interactions (DDIs). Endogenous OATP1B biomarkers, such as coproporphyrin I (CP‐I), are strongly predicted to improve DDI prediction in drug development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PBPK model analysis of the clinical CP‐I data successfully predict OATP1B‐mediated DDIs using probe drugs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The value of the most important DDI parameter, K_i,OATP1B, estimated by PBPK model‐based analysis of clinical CP‐I data, was able to overcome the discrepancy between the in vitro and in vivo effects of CysA on OATP1B, and could be applied to predict the change in the blood concentration time profiles of OATP1B probe drugs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The collection of endogenous OATP1B biomarker data is a feasible strategy to capture DDI potential. PBPK models aids in the prediction of its clinical impact more precisely, help to reduce risk in drug development, and impact the regulatory decision tree for DDI risk assessment.     

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remibrutinib is an irreversible Bruton’s Tyrosine Kinase inhibitor and moderate CYP3A4 substrate to be administered with caution with strong inhibitors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug‐drug interaction (DDI) risk of remibrutinib as a victim with CYP3A4 inhibitors.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Using a specifically tailored study design, most model‐relevant pharmacokinetic (PK) parameters were determined, including fractions of the dose escaping intestinal and hepatic first‐pass metabolism, absolute bioavailability, systemic drug clearance, apparent volume of distribution at steady‐state, and fraction of the drug metabolized via CYP3A4.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The clinical study design offers opportunities to obtain important PK parameters, which enabled physiologically‐based pharmacokinetic (PBPK) model building of complex PK compounds. Taken together, the PK parameters and the PBPK simulations allowed robust DDI predictions of untested scenarios.     

Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC₅₀] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A new therapeutic agent, omecamtiv mecarbil (OM), increases cardiac contractility by prolonging systolic ejection time, however, there is no published data assessing its pro‐arrhythmic risks.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pro‐arrhythmic risk assessment of OM in in vitro and ex vivo safety pharmacology models compliant with International Conference on Harmonization S7B guideline and Comprehensive In Vitro Proarrhythmia Assay initiative.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Comprehensive in vitro pro‐arrhythmic risk assays demonstrate that OM has low pro‐arrhythmic risk and translate into clinical safety observations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Low pro‐arrhythmic risks consistently identified in preclinical in vitro models translate well into clinical observations (i.e., negative preclinical pro‐arrhythmic findings can predict negative clinical outcomes).     

The bioequivalence of fixed‐dose combination tablets of bisoprolol and ramipril and its drug‐drug interaction potential

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed‐dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open‐label, bioequivalence (BE) studies and one drug‐drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two‐way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (C_max) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of C_max for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well‐tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co‐administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Bisoprolol (BISO) and ramipril (RAMI) have both well‐characterized pharmacokinetic (PK) properties, however, clinical studies for this fixed‐dose combination (FDC) are limited and as per our knowledge, a potential of PK drug‐drug interactions (DDIs) between both compounds has not been evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The clinical program was focused on the evaluation of bioequivalence (BE) for two strengths of novel FDCs containing BISO/RAMI in comparison with their free‐combinations and evaluation of potential PK interaction between BISO and RAMI.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

An absence of PK interaction between BISO and RAMI has been demonstrated in the DDI study. The BE studies provided information about in vivo behavior of the FDC, as well as additional PK, and statistical and safety data for BISO and RAMI.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

FDC containing BISO and RAMI may reduce tablet burden, improve adherence to treatment, and blood pressure control in patients with hypertension. The administration of BISO and RAMI is not associated with a risk of PK interaction between both compounds.     

Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP,OATP1B1, and OAT3 transporters

Tolvaptan (TLV) was US Food and Drug Administration (FDA)‐approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM‐4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM‐4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM‐4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (C_max) were 1.54 (90% CI 1.26–1.88) and for area under the concentration‐time curve from time 0 to the time of the last measurable concentration (AUC_t) were 1.69 (90% CI 1.34–2.14), indicating no clinically significant interaction. DM‐4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM‐4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The US Food and Drug Administration (FDA) created a guidance for estimating the potential for clinically relevant drug‐drug interactions (DDIs) at BCRP, OATP1B1, OAT3, and other transporters. The predictions use various assumptions. For example, for BCRP, it is assumed that inhibitory drug is completely soluble in 250 ml. For OATP1B1 and OAT3, if plasma protein binding for inhibitor is greater than 99%, then fraction unbound is set to 1%.

• WHAT QUESTION DID THIS STUDY ADDRESS?

These studies addressed if the predictions for clinically relevant DDIs at BCRP for tolvaptan and at OATP1B1 and OAT3 for the oxobutyric acid metabolite were correct and interactions were observed.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

As there were no clinically relevant interactions, the results support the consideration of drug solubility for BCRP and actual plasma protein binding for OATP1B1 and OAT3 in the predictions of clinically relevant DDIs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Assumptions used in the prediction of clinically relevant DDIs would be revised.     

Application of a PBPK model to elucidate the changes of systemic and liver exposures for rosuvastatin,carotegrast, and bromfenac followed by OATP inhibition in monkeys

The impact of organic anion‐transporting polypeptide (OATP) inhibition on systemic and liver exposures of three OATP substrates was investigated in cynomolgus monkeys. A monkey physiologically‐based pharmacokinetic (PBPK) model was constructed to describe the exposure changes followed by OATP functional attenuation. Rosuvastatin, bromfenac, and carotegrast were administered as a single intravenous cassette dose (0.5 mg/kg each) in monkeys with and without predosing with rifampin (RIF; 20 mg/kg) orally. The plasma exposure of rosuvastatin, bromfenac, carotegrast, and OATP biomarkers, coproporphyrin I (CP‐I) and CP‐III were increased 2.3, 2.1, 9.1, 5.4, and 8.8‐fold, respectively, when compared to the vehicle group. The liver to plasma ratios of rosuvastatin and bromfenac were reduced but the liver concentration of the drugs remained unchanged by RIF treatment. The liver concentrations of carotegrast, CP‐I, and CP‐III were unchanged at 1 h but increased at 6 h in the RIF‐treated group. The passive permeability, active uptake, and biliary excretion were characterized in suspended and sandwich‐cultured monkey hepatocytes and then incorporated into the monkey PBPK model. As demonstrated by the PBPK model, the plasma exposure is increased through OATP inhibition while liver exposure is maintained by passive permeability driven from an elevated plasma level. Liver exposure is sensitive to the changes of metabolism and biliary clearances. The model further suggested the involvement of additional mechanisms for hepatic uptakes of rosuvastatin and bromfenac, and of the inhibition of biliary excretion for carotegrast, CP‐I, and CP‐III by RIF. Collectively, impaired OATP function would not reduce the liver exposure of its substrates in monkeys.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Challenges remain in understanding the impact of hepatic uptake transporter, OATPs, on plasma and liver concentrations for OATP substrate drugs with distinct pharmacokinetic (PK) profiles and elimination routes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How do hepatic active transport, metabolism, biliary excretion, and passive permeability impact the systemic and liver exposure?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study elucidates the important roles of hepatic active transport in determining drug plasma and liver concentrations and the translation of in vitro data to in vivo using the physiologically‐based PK modeling approach.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The disconnection between plasma concentration and liver exposure followed by OATP activity reduction can explain the PK/pharmacodynamic relationship for the liver‐targeted drugs.     

Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin,a novel dual‐acting glucokinase activator

Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end‐stage renal disease (ESRD). Based on the results from physiologically‐based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (C_max) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two‐part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for C_max and 1.11 for AUC. The elimination half‐life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well‐tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Currently, there are limited safe and effective anti‐hyperglycemia treatments for patients with diabetic kidney disease (DKD) and end‐stage renal disease (ESRD). Dorzagliatin has exhibited favorable absorption, distribution, metabolism, and excretion/drug metabolism and pharmacokinetic properties with good safety and efficacy profiles in multiple preclinical and clinical studies, demonstrating its potential as a novel glucose sensitizer for the treatment of type 2 diabetes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The impact of renal impairment (RI) on dorzagliatin pharmacokinetics (PKs). Whether dorzagliatin can be used in patients with DKD without dose adjustment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RI had no significant impact on dorzagliatin PKs. Dorzagliatin can be used without dose adjustment in patients with DKD at any stage, including ESRD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A reduced study was designed based on regulatory guidance. Physiologically‐based pharmacokinetic (PBPK) modeling accurately predicted minimal impact of RI on dorzagliatin exposure, further supporting the study design. Subsequent clinical study results confirmed in silico prediction and validated the PBPK model. Therefore, integrating computational approach using scientifically well‐founded PBPK models can be powerful in critical decision making in drug development to reduce expenses and increase confidence.     

Single‐dose of LC51‐0255, a selective S1P1 receptor modulator,showed dose‐dependent and reversible reduction of absolute lymphocyte count in humans

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach in treating autoimmune diseases. LC51‐0255 is a sphingosine‐1‐phosphate 1 receptor modulator, which is known to decrease the peripheral ALC. We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability profiles of LC51‐0255 after a single oral administration in healthy subjects. A randomized, double‐blind, placebo‐controlled, dose‐escalation study was conducted in 50 healthy subjects. Each subject orally received LC51‐0255 (0.25, 0.5, 1, 2, or 4 mg) or its matching placebo in an 8:2 ratio. Blood and urine samples were collected to assess the PKs, and PDs was evaluated using peripheral ALC and 24‐h hourly heart rate data. Safety and tolerability were assessed by monitoring treatment emergent adverse events (TEAEs), vital signs, 12‐lead electrocardiogram (ECG), continuous 24‐h ECG (via Holter monitoring), clinical laboratory tests, ophthalmologic tests, pulmonary function tests, and physical examinations. A single dose of LC51‐0255 reduced ALC and heart rate in a reversible and dose‐dependent manner. Systemic exposure of LC51‐0255 increased dose‐dependently and its half‐life ranged from 72.2 to 134.0 h. ALC and the systemic exposure of LC51‐0255 seemed to be negatively correlated. LC51‐0255 was well‐tolerated up to 2 mg, and the most common TEAE was bradycardia. The results of this study suggest that LC51‐0255 can be developed into a beneficial treatment option for autoimmune disease.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach to treat autoimmune diseases. Sphingosine‐1‐phosphate 1 (S1P₁) receptor modulator reduces peripheral ALC by preventing the recirculation of lymphocytes from lymphatic tissue to target organs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed this study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability profiles of LC51‐0255, a novel S1P₁ receptor modulator, in humans.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results showed that LC51‐0255 has a relatively long half‐life, is well‐tolerated, and reduces ALC in a dose‐dependent and reversible manner.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results provide evidence that a single dose of LC51‐0255 can be further developed into a beneficial treatment option for patients with autoimmune disease.     

A phase I,randomized, double‐blind,placebo‐controlled,single‐ and multiple dose escalation study evaluating the safety,pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor,in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Na_vs), such as Na_v1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Na_v1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na_v1.8 inhibitors as pain treatments.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective sodium channel (Na_v) inhibitors have been proposed as an alternative to opioids for pain management. Their potential, however, has yet to be confirmed, as none of the multiple selective Na_v inhibitors that have been investigated for pain management has reached the market.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We investigated the safety, tolerability, and initial analgesic effects of VX‐128, a novel and highly selective Na_v1.8 inhibitor, in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study to describe clinical data obtained on the highly selective Na_v1.8 inhibitor VX‐128, and the first to report analgesic effects of this selective Na_v inhibitor in humans. VX‐128 administered as a single dose was well‐tolerated, but dose‐limiting skin rashes occurred after multiple doses resulting in a premature study halt. Although the study had a parallel design and was not necessarily powered to detect pharmacodynamic effects, nociceptive test results suggest that VX‐128 leads to dose‐dependent analgesic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings substantiate research that is performed on evaluating selective Na_v1.8 inhibitors as treatment for pain, and suggests that the cold pressor‐ and pressure pain models are suitable to evaluate selective Na_v1.8 inhibitors.     

Effect of difelikefalin,a selective kappa opioid receptor agonist,on respiratory depression: A randomized,double‐blind,placebo‐controlled trial

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small‐peptidic structure limits CNS entry, minimizing potential CNS‐mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single‐center, randomized, double‐blind, placebo‐controlled, three‐way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end‐tidal carbon dioxide (ETCO₂) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO₂) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO₂ or reduced SpO₂ primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4‐h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO₂, SpO₂, or respiratory rate. The most commonly reported treatment‐emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Severe respiratory depression is a life‐threatening complication of inappropriate use of mu opioid receptor agonists. Difelikefalin, a peripherally restricted kappa opioid receptor (KOR) agonist, has not demonstrated evidence of compromised respiratory safety.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated whether difelikefalin, a selective and potent KOR agonist, induces respiratory depression.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study helps to expand on the safety profile for difelikefalin. Difelikefalin did not produce respiratory depression in healthy volunteers at doses that were 2 to 10 times higher than those observed to be therapeutically effective in clinical trials of patients with chronic kidney disease–associated pruritus.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

KOR agonists may be potentially safe and effective therapeutics. Difelikefalin is currently being evaluated for chronic kidney disease‐associated pruritus and other chronic pruritic conditions.     

Utilization of physiologically‐based pharmacokinetic model to assess disease‐mediated therapeutic protein‐disease‐drug interaction in immune‐mediated inflammatory diseases

It is known that interleukin‐6 (IL‐6) can significantly modulate some key drug‐metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically‐based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP‐DIs) in patients with immune‐mediated inflammatory diseases (IMIDs) with elevated systemic IL‐6 levels when treated by anti‐IL‐6 therapies. Literature data of IL‐6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL‐6 level and local IL‐6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL‐6 signaling pathway by an anti‐IL‐6 treatment, the area under plasma concentration versus time curves (AUCs) of S‐warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn’s disease and ulcerative colitis treated with an anti‐IL‐6 therapy, the lowering of the elevated IL‐6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP‐DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP‐DI in patients with elevated IL‐6 levels when an anti‐IL‐6 therapeutic is used with concomitant small‐molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Interleukin‐6 (IL‐6) may significantly modulate some key drug‐metabolizing enzymes, including phase I cytochrome P450s (CYPs). A physiologically‐based pharmacokinetic (PBPK) model was developed to predict the impact of elevated IL‐6 level and anti‐IL‐6 mAb treatment on multiple CYP enzymes in patients with rheumatoid arthritis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The aforementioned PBPK model was expanded to assess potential therapeutic protein drug interactions (TP‐DIs) between anti‐IL‐6 treatment and CYP substrate drugs in different immune‐mediated inflammatory disease (IMID) populations with elevated IL‐6 levels. For the inflammatory bowel disease (IBD) populations, modulation effects from elevated IL‐6 levels in the local gastrointestinal tract were taken into consideration. The potential additive modulation effect on CYPs from concomitant cancer‐IMID situation was also assessed. Furthermore, simulations at different hypothetical IL‐6 levels were performed to identify the IL‐6 levels, which would result in weak, moderate, and strong CYP modulation effects based on the definitions in the US Food and Drug Administration (FDA) drug‐drug interaction guidance.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PBPK platform model was expanded to assess the potential TP‐DIs during anti‐IL‐6 treatment in several IMIDs including systemic lupus erythematosus, ulcerative colitis, Crohn’s disease, type 1 diabetes, and cancer‐IMID comorbidity. The high local IL‐6 levels in patients with IBD were predicted to result in extra inhibition effect on the abundances of intestinal CYPs. Patients with cancer‐IMID manifested further decrease in systemic exposures of CYP substrate drugs compared with patients with IMID only. Cutoff values of IL‐6 level which would result in different levels of CYP modulation effect were identified.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This PBPK model approach may serve as conceptual framework and workflow process to evaluate the modulation effect on CYPs in patients by therapeutic modalities which can significantly result in altered levels of proinflammatory cytokines during the treatment period.     

Hybrid physiologically‐based pharmacokinetic model for remdesivir: Application to SARS‐CoV‐2

A novel coronavirus, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) or coronavirus disease 2019 (COVID‐19), has caused a pandemic that continues to cause catastrophic health and economic carnage and has escalated the identification and development of antiviral agents. Remdesivir (RDV), a prodrug and requires intracellular conversions to the active triphosphate nucleoside (TN) has surfaced as an active anti‐SARS‐CoV‐2 drug. To properly design therapeutic treatment regimens, it is imperative to determine if adequate intracellular TN concentrations are achieved in target tissues, such as the lungs. Because measurement of such concentrations is unrealistic in patients, a physiologically‐based pharmacokinetic (PBPK) model was developed to characterize RDV and TN disposition. Specifically, a hybrid PBPK model was developed based on previously reported data in humans. The model represented each tissue as a two‐compartment model—both extracellular and intracellular compartment wherein each intracellular compartment contained a comprehensive metabolic model to the ultimate active metabolite TN. Global sensitivity analyses and Monte‐Carlo simulations were conducted to assess which parameters and how highly sensitive ones impacted peripheral blood mononuclear cells and intracellular lung TN profiles. Finally, clinical multiple‐dose regimens indicated that minimum lung intracellular TN concentrations ranged from ~ 9 uM to 4 uM, which suggest current regimens are effective based on in vitro half‐maximal effective concentration values. The model can be used to explore tissue drug disposition under various conditions and regimens, and expanded to pharmacodynamic models.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There is limited information on the tissue distribution and metabolism of remdesivir (RDV)—an antiviral agent recently US Food and Drug Administration (FDA)‐approved for patients with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)—and none in the patients.

• WHAT QUESTION DID THIS STUDY ADDRESS?

RDV is known to undergo intracellular conversion to an active triphosphate nucleoside (TN) metabolite, and the computational investigation used a physiologically‐based pharmacokinetic (PBPK) of RDV to characterize the tissue distribution of RDV and the intracellular metabolite kinetics and the production of TN.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PBPK model of RDV characterizes the extent of RDV tissue distribution and the associated intracellular metabolism in target tissues, such as the lungs. The model simulations can be used to assess the efficacy of current clinical dosing regimens based on TN intracellular concentration profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The PBPK model of RDV serves as a foundation to rationally design clinical dosing protocols for RDV and may be extended to viral dynamic and pharmacodynamic models, and further support the development of PBPK models for other antivirals used for SARS‐CoV‐2.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

Effects of 5‐HT₃ receptor antagonists on cisplatin‐induced kidney injury

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin‐induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5‐HT₃ receptor antagonists used clinically for cisplatin‐induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5‐HT₃ receptor antagonists in a mouse model of cisplatin‐induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first‐generation 5‐HT₃ receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first‐generation 5‐HT₃ receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second‐generation 5‐HT₃ receptor antagonist. These results suggest that compared with the first‐generation antagonists, second‐generation 5‐HT₃ receptor antagonists do not worsen cisplatin‐induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The involvement of the multidrug and toxin release (MATE) transporter in cisplatin‐induced kidney injury has been reported. The MATE transporter is involved in the excretion of not only cisplatin but also ondansetron, a 5‐HT₃ receptor antagonist used as an antiemetic; however, the effects of 5‐HT₃ receptor antagonists used clinically for cisplatin‐induced renal injury have not been elucidated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The aim of this study was to investigate the effects of 5‐HT₃ receptor antagonists in a mouse model of cisplatin‐induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results suggest that compared with the first‐generation antagonists, second‐generation 5‐HT₃ receptor antagonists do not worsen cisplatin‐induced acute kidney injury.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Promoting the use of second‐generation 5‐HT₃ receptor antagonists is expected to reduce the number of patients who develop cisplatin‐induced renal damage.     

A randomized,double‐blind,placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced prolongation of the QT interval has the potential to cause severe, potentially fatal ventricular arrhythmias. A number of antimicrobial agents, including fluoroquinolones and macrolides, are associated with a low, but clinically significant increased risk of QT prolongation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval in healthy subjects to determine if there were any potentials for proarrhythmic effects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study found that durlobactam had a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Because durlobactam had a low risk for prolonging the QT interval alone and when co‐administered with sulbactam, clinicians should be confident in administering the combination without risk for proarrhythmic effects.     

Evaluation of the pharmacokinetics of trazpiroben (TAK‐906) in the presence and absence of the proton pump inhibitor esomeprazole

Trazpiroben, a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis, displays decreasing solubility with increasing pH. This single‐sequence, open‐label, two‐period, crossover study evaluated the effect of esomeprazole, a proton pump inhibitor that raises gastric pH, on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults ({"type":"clinical-trial","attrs":{"text":"NCT03849690","term_id":"NCT03849690"}}NCT03849690). In total, 12 participants were enrolled and entered period 1 (days 1–3), receiving a single oral dose of trazpiroben 25 mg on day 1. After a 4‐day washout, participants then entered period 2 (days 8–13) and received esomeprazole 40 mg once daily on days 8–12, with a single oral dose of trazpiroben 25 mg co‐administered 1 h post esomeprazole dosing on day 11. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC_∞) and maximum plasma concentration (C_max) values were generally similar when trazpiroben was administered alone versus alongside esomeprazole (AUC_∞, 44.03 vs. 38.85 ng h/ml; C_max, 19.76 vs. 17.24 ng/ml). Additionally, the associated geometric mean ratio (GMR; co‐administration: administration alone) 90% confidence intervals (CIs) suggested no clinically meaningful difference between treatment groups (AUC_∞, GMR 0.88, 90% CI 0.78–1.00; C_max, 0.87, 90% CI 0.70–1.09). Mean apparent first‐order terminal elimination half‐life values were similar between treatments, illustrating co‐administration with esomeprazole had minimal effect on trazpiroben elimination. Trazpiroben was well‐tolerated in healthy adults following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported. The lack of evidence of any clinically meaningful drug–drug interaction supports the co‐administration of esomeprazole with trazpiroben.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Gastroparesis is a gastric motility disorder typified by delayed gastric emptying without mechanical obstruction, with affected patients experiencing a range of gastrointestinal symptoms. Patients with gastroparesis may experience symptom overlap with, or comorbid, gastroesophageal reflux disease. Proton pump inhibitors (PPIs), which raise gastric pH, are frequently used to provide symptomatic relief. Trazpiroben is a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis. Given that trazpiroben displays decreasing solubility with increasing pH, the potential for a drug–drug interaction (DDI) with a PPI was evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of the PPI esomeprazole on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study demonstrated no evidence of any clinically meaningful DDI between trazpiroben and esomeprazole. Trazpiroben was well‐tolerated following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current treatment landscape for gastroparesis is limited, with use of available therapies restricted by safety concerns. Our findings support the potential co‐administration of trazpiroben and esomeprazole, indicating that trazpiroben could represent a promising treatment option for patients with gastroparesis who are receiving PPI therapy.     

Translational and pharmacokinetic‐pharmacodynamic application for the clinical development of GDC‐0334, a novel TRPA1 inhibitor

GDC‐0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC‐0334 were evaluated in this first‐in‐human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC‐0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK‐PD of GDC‐0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC‐0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target‐engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose‐concentration‐effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC‐0334 was administered with food. The inhibitory effect of GDC‐0334 on the AITC‐induced DBF biomarker exhibited a clear sigmoid‐Emax relationship with GDC‐0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC‐0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GDC‐0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling strategy could be implemented in a systematic and step‐wise manner to build and learn from emerging data for early clinical development.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can noncompartmental and population‐based analyses be used to describe the PK and PD characteristics of GDC‐0334 in preclinical and clinical studies?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

GDC‐0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC‐0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC‐0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK‐PD relationship.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The models developed based on TRPA1 agonist‐induced dermal blood flow inhibition data can be used to predict PK‐PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.     

First‐in‐human study of milvexian,an oral,direct, small molecule factor XIa inhibitor

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T_1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Factor XI (FXI) amplifies thrombin generation and has a limited role in hemostasis. Targeted FXI inhibition may reduce the burden of vascular and thromboembolic diseases while preserving hemostasis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the selective, direct, small molecule FXIa inhibitor milvexian.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single and multiple ascending doses of milvexian up to 500 mg were generally safe and well‐tolerated, with no clinically significant bleeding events. Milvexian plasma concentration was dose proportional at doses up to 200 mg q.d. The milvexian half‐life is suitable for q.d. or b.i.d. dosing. Milvexian exhibited low renal excretion and low overall variability in PK and PD parameters.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.