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.     

Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin,a BCRP substrate,with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUC_inf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUC_last), and maximum observed plasma concentration (C_max), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUC_inf and C_max were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Omecamtiv mecarbil (OM) is a cardiac myosin activator and is currently under investigation for the treatment of heart failure with reduced ejection fraction.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the drug‐drug interaction (DDI) potential of OM on the pharmacokinetics of rosuvastatin, a BCRP substrate, using a clinical study and a physiologically‐based pharmacokinetic (PBPK) modeling approach.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The clinical study and PBPK modeling analyses confirm that OM is expected to be a weak inhibitor of BCRP in the clinical setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the DDI potential of single doses of OM for BCRP substrates from a clinical study and demonstrates the importance of the PBPK modeling approach to investigate DDI effects following multiple doses of OM at therapeutic concentrations.     

Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice‐daily on days 3–11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5‐hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix–omeprazole drug–drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice‐daily for 9 days increased omeprazole exposure by 1.8‐fold and decreased the metabolite‐to‐parent ratio for 5‐hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite‐to‐parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2‐ to 2.5‐fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5‐hydroxyomeprazole decreased by 20%–30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3‐fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19‐mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Elagolix is an inhibitor of P‐glycoprotein (P‐gp) and a weak‐to‐moderate inducer of cytochrome P450 3A (CYP3A4). In vitro, elagolix was identified as a possible inhibitor of CYP2C19 with potential to increase plasma concentrations of drugs that are substrates of CYP2C19 if they are coadministered with elagolix.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy subjects with different CYP2C19 genotypes and are P‐gp and/or CYP3A4 potentially involved in the interaction between elagolix and omeprazole?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that elagolix is a weak inhibitor of CYP2C19 and exposure of other CYP2C19 substrates may be increased upon coadministration with elagolix. These results also suggest P‐gp, CYP3A4, and/or another unknown mechanism may also be potential mechanisms for drug interactions with omeprazole.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Future DDI studies with omeprazole as a CYP2C19 substrate should consider that omeprazole may exhibit complex drug interactions due to multiple mechanisms mediating metabolism and transport, which may confound the interpretation of study results.     

Pharmacokinetics of asciminib in the presence of CYP3A or P‐gp inhibitors,CYP3A inducers,and acid‐reducing agents

Asciminib is a first‐in‐class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P‐glycoprotein (P‐gp) and possesses pH‐dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P‐gp inhibitors, CYP3A inducers and acid‐reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (C_max) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40‐fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13–15%) and the strong P‐gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in C_max. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P‐gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin‐containing drug formulations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Asciminib is a first‐in‐class BCR::ABL1 inhibitor, specifically targeting the ABL myristoyl pocket, and a substrate of CYP3A4 and P‐gp. Asciminib displays pH‐dependent solubility in aqueous solution.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug–drug interaction risk of asciminib as a victim with CYP3A inhibitors, CYP3A inducers, P‐gp inhibitors, and acid‐reducing agents (ARAs).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Asciminib as a victim was weakly affected by concomitantly administered P‐gp inhibitors, strong CYP3A inhibitors, strong CYP3A inducers, or ARAs. However, a substantial effect of cyclodextrin (as an excipient in itraconazole oral solution) was observed; indirect evidence showed that cyclodextrin markedly decreased asciminib bioavailability.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results support the concomitant use of CYP3A and P‐gp inhibitors, CYP3A inducers and ARAs in patients treated with asciminib. Care should be exercised when using itraconazole oral solution or other cyclodextrin‐containing formulations in clinical studies due to their potential impact on absorption of orally co‐administered compounds.     

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.     

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.     

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.     

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end‐stage renal disease

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end‐stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact‐PTH (iPTH) level with blood tacrolimus concentration in patients with end‐stage renal disease just before kidney transplantation. Forty‐eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co‐administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Tacrolimus is primarily metabolized by cytochrome P450 (CYP) 3A4/5 and the pharmacokinetics is affected by CYP3A5 polymorphism. Recently, intact parathyroid hormone (PTH) has been shown to downregulate CYP3A expression at the mRNA level.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Do CYP3A5 polymorphism and serum intact PTH influence the tacrolimus concentration/dose per body weight before kidney transplantation in patients with end‐stage renal failure?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

When designing dose of tacrolimus for patients scheduled to undergo renal transplantation, it may be important to consider not only the CYP3A5 phenotype but also the serum intact PTH level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Confirming the CYP3A5 phenotype and serum intact PTH level could allow physicians to control blood concentration of tacrolimus from an earlier stage before transplantation. This may contribute to prevent rejection and graft‐versus‐host disease in patients who undergo renal transplantation and to prolong the post‐transplant survival of the transplanted kidney.     

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.     

Model‐based dose selection to inform translational clinical oncology development of WNT974, a first‐in‐class Porcupine inhibitor

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. The conventional approach for dose selection in small‐molecule oncology trials is based on the maximum tolerated dose (MTD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to inform the clinical development path and selection of the recommended dose for expansion (RDE) for a first‐in‐class oncology molecule.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A model‐based approach can be effectively used to integrate pharmacokinetic (PK), pharmacodynamic and safety data and inform RDE selection in oncology drug development.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This model‐based approach integrated population PK and exposure–response analyses of biomarker and safety to determine the RDE, rather than the conventional MTD approach. The strategy can be applied to support translational clinical oncology development, and dose selection in early oncology trials to inform later phase clinical development and study design.     

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

To improve predictions of concentration‐time (C‐t) profiles of drugs, a new physiologically based pharmacokinetic modeling framework (termed ‘PermQ’) has been developed. This model includes permeability into and out of capillaries, cell membranes, and intracellular lipids. New modeling components include (i) lumping of tissues into compartments based on both blood flow and capillary permeability, and (ii) parameterizing clearances in and out of membranes with apparent permeability and membrane partitioning values. Novel observations include the need for a shallow distribution compartment particularly for bases. C‐t profiles were modeled for 24 drugs (7 acidic, 5 neutral, and 12 basic) using the same experimental inputs for three different models: Rodgers and Rowland (RR), a perfusion‐limited membrane‐based model (K_p,mem), and PermQ. K_p,mem and PermQ can be directly compared since both models have identical tissue partition coefficient parameters. For the 24 molecules used for model development, errors in V_ss and t _1/2 were reduced by 37% and 43%, respectively, with the PermQ model. Errors in C‐t profiles were reduced (increased EOC) by 43%. The improvement was generally greater for bases than for acids and neutrals. Predictions were improved for all 3 models with the use of parameters optimized for the PermQ model. For five drugs in a test set, similar results were observed. These results suggest that prediction of C‐t profiles can be improved by including capillary and cellular permeability components for all tissues.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Compared to compartmental models, concentration‐time profiles of drugs are often not well‐predicted by perfusion‐limited PBPK models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can C‐t profiles be better predicted by including capillary, cellular and membrane permeability in a new PBPK framework?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that variable capillary permeability for different tissues is an important anatomical component for drug distribution. Apparent permeability and membrane partitioning can be used to model clearances in and out of membranes. Early distribution kinetics observed in the C‐t profile of basic drugs indicates that an additional shallow distribution compartment is necessary. Parameters optimized for input into the new PermQ framework also decrease the prediction errors in perfusion‐limited PBPK models.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved prediction of drug concentration‐time profiles with new modeling frameworks such as the PermQ model can result in improved therapeutic outcomes for healthy and special populations.     

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.     

Emergency department admissions induced by drug–drug interactions in the elderly: A cross‐sectional study

The elderly people are increasingly exposed to polymedication and therefore to the risks of drug–drug interactions (DDIs). However, there are few data available on the clinical consequences of these drug combinations. We investigated the impact of the various DDIs classified as severe in terms of emergency admissions in the elderly. A cross‐sectional study was conducted using information from the emergency department admissions of Bordeaux University Hospital between September 2016 and August 2017. Events of interest were frequency of concomitant uses of interacting drugs that are contraindicated or warned against and frequency of emergency admissions due to contraindicated or warned against concomitant uses of interacting drugs. Five thousand, eight hundred sixty (5860) admissions to the emergency department were analyzed. A total of 375 (6.4%) contraindicated or warned against concomitant uses were identified, including 163 contraindicated (43.5%) and 212 warned against (56.5%). Reason for admission appeared likely related to the underlying DDI in 58 cases. Within these, 36 admissions were assessed as probably due to a DDI (0.6% of hospitalizations) and 22 as certainly (0.4% of hospitalizations). Of these, there were 24 (45%) admissions related to a long QT syndrome (LQTS), nine (16%) related to a drug overdose, and eight (14%) related to a hemorrhage. An antidepressant was involved in 22 of the 24 cases of LQTS. Seven of the eight cases of hemorrhage involved the antithrombotic agents / non‐steroidal anti‐inflammatory drugs combination. Elderly patients admitted to emergency departments are particularly exposed to high‐risk potential DDIs. These drug combinations lead mainly to LQTS and involve certain antidepressants.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The prevalence of polypharmacy is high in elderly patients admitted to the emergency department, which theoretically exposes this population to many potential drug–drug‐interactions (DDIs).

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the real clinical impact of potential DDIs classified as severe?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Reason for emergency admission appeared likely related to a potential DDI for 0.4–1% of elderly patients. Among the drugs involved, psychotropic drugs and in particular two antidepressants: citalopram and escitalopram, are the drugs which seem to cause the most hospitalizations. Particularly due to the risk of long QT syndrome.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

We strongly recommend systematizing electrocardiogram monitoring in all elderly patients admitted to the emergency department and treated with an antidepressant.     

Influence of CYP2D6 metabolizer status on ondansetron efficacy in pediatric patients undergoing hematopoietic stem cell transplantation: A case series

Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In adults, ondansetron is not as effective for chemotherapy‐induced nausea and vomiting (CINV) in CYP2D6 ultrarapid metabolizers (UMs) compared to non‐UMs. Ondansetron is a medication commonly prescribed to pediatric patients, especially for CINV.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Our study describes the efficacy of ondansetron for CINV in three pediatric CYP2D6 UMs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Pediatric CYP2D6 UMs experienced more emesis when taking ondansetron for CINV on days where they did not receive opioids than expected, similar to findings in adults.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Based on these findings, at our institution, any patient undergoing a bone marrow transplant that is a CYP2D6 UM will receive granisetron rather than ondansetron; this practice may be applicable to pediatric patients at other institutions.     

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.     

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.     

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Typical cardiovascular studies usually employ timepoint analysis. Published in vivo corrected QT (QTc) assay data has exhibited variability in QTc sensitivity that results in challenges in nonclinical‐clinical assessment of translation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Comparison of nonclinical timepoint and concentration QTc (C‐QTc) analyses and how it relates to clinical moxifloxacin data.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Dog and non‐human primate (NHP) QTc timepoint and C‐QTc analyses detect QTc internal prolongation, have equivalent sensitivity, and improve confidence in these models for proarrhythmic risk mitigation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Risk assessment in nonclinical models translates well to human thorough QT (TQT) data for moxifloxacin. The new data highlights the value of a high‐quality dog or NHP QTc assay to support clinical risk assessment and regulatory decision making.     

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The clinical trials in vulnerable populations, such as infants, face challenges, including the limited blood volume due to the small bodies. In Japan, the necessity of pediatric indications has been discussed against the background of a lack of Japanese pediatric data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This simulation study aimed to apply a model‐based approach to the development of antibiotics for pediatric patients to reduce practical and ethical constraints.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The model‐based approach to sampling optimization provided a maximization of pharmacokinetic information with a minimum burden on infants and young children.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The approach will support future pediatric clinical trials and investigator‐initiated trials, as well as provide the valuable information for therapeutic drug monitoring and the administration plans for antibiotics in clinical settings.     

Identification of small molecules that mitigate vincristine‐induced neurotoxicity while sensitizing leukemia cells to vincristine

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose‐limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR‐induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human‐induced pluripotent stem cell‐derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR’s antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vincristine (VCR) is a widely prescribed drug, but its use is limited by its main side effect, neurotoxicity. There are currently no strategies to mitigate VCR neurotoxicity without altering its antileukemic effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to improve VCR efficacy while reducing its main side effect, neurotoxicity?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The present study shows for the first time the possibility of reduced VCR ‐induced neurotoxicity while improving VCR anti‐leukemia effect by using small molecules.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current translational study could permit a safer and more efficient use of VCR.     

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first‐in‐human trial of the activated Factor XII inhibitor garadacimab (CSL312)

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein–kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first‐in‐class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first‐in‐human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose‐related PD effects were observed (e.g., a mechanism‐based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically‐based pharmacokinetic (mPBPK) models with target‐mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa‐mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Models based on physiology and mechanisms of action can be highly useful in translating pharmacokinetic/pharmacodynamic (PK/PD) data from animal studies to expectations in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis sought to select doses for investigation in a phase I, first‐in‐human trial of garadacimab (CSL312), a first‐in‐class, fully human, immunoglobulin G4 monoclonal antibody that targets FXIIa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis demonstrated how a mechanism‐based PK/PD model describing the relationship between drug administration and pharmacologic response observed in cynomolgus monkeys was generated and extrapolated to select doses for investigation in a phase I, first‐in‐human trial of garadacimab. The detailed explanation of the modeling and extrapolation methodology used in this study provides guidance to future researchers selecting doses for phase I, first‐in‐human trials of monoclonal antibodies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the importance and utility of insightful, physiologic, and mechanistic mathematical modeling in conjunction with robust animal data for translation of PK/PD and accurate prediction of first‐in‐human dosing for clinical trials.