Relationship of hemoglobin level and plasma coproporphyrin‐I concentrations as an endogenous probe for phenotyping OATP1B

Plasma coproporphyrin‐I (CP‐I) concentration is used as a sensitive and selective endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B) activity in many studies. CP‐I is produced in the process of heme synthesis, but the relationship between plasma CP‐I concentrations and heme synthesis activity is unknown. In this study, we evaluated the relationship between plasma CP‐I concentration and hemoglobin level as a biomarker of heme synthesis activity. The data of 391 subjects selected from the Japanese general population were analyzed. One hundred twenty‐six participants had OATP1B1*15 allele, 11 of whom were homozygous (OATP1B1*15/*15). Multiple regression analysis identified hemoglobin level as an independent variable associated with plasma CP‐I concentration (p < 0.0001). A significant positive correlation was observed between hemoglobin level and plasma CP‐I concentration in participants without OATP1B1*15 allele (n = 265; r _s = 0.35, p < 0.0001) and with OATP1B1*15 allele (n = 126; r _s =0.27, p = 0.0022). However, Kruskal–Wallis test showed no large difference in Kruskal–Wallis statistics between the distribution of plasma CP‐I concentrations and that of ratio of plasma CP‐I to hemoglobin among six OATP1B1 polymorphism groups. These findings suggest that the hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not required when using basal plasma CP‐I concentration for phenotyping OATP1B activity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Coproporphyrin‐I (CP‐I) in plasma is a sensitive and specific endogenous biomarker for phenotyping organic anion transporting polypeptides 1B (OATP1B), and has been used for phenotyping OATP1B activity, such as in clinical drug‐drug interaction studies. CP‐I is produced during the process of heme synthesis, indicating that correction of plasma CP‐I concentration by hemoglobin level as an indicator of heme synthesis activity may be needed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does correction by hemoglobin level improve the usefulness of CP‐I as a probe for OATP1B phenotyping?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Hemoglobin level was identified as an independent variable associated with plasma CP‐I concentrations. However, no large difference in Kruskal–Wallis statistics was observed between the distribution of plasma CP‐I concentrations and that of CP‐I/Hb ratio among six OATP1B1 polymorphism groups.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not needed when using plasma CP‐I concentration for phenotyping OATP1B activity.     

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.     

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.     

Evaluation of the safety,tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first‐in‐human study (in which most of the HVs were non‐Asian). HVs randomly received a single dose of 200–600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200–400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well‐tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half‐life ranged from 3.66 to 14.6 h. A single dose of 200–600 mg and multiple doses of 200–400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non‐Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

RO7049389 is a small molecule that is being developed as an orally administered solid dosage formulation for the treatment of chronic hepatitis B infection. The healthy volunteers (HVs) part of the first‐in‐human study of RO7049389 was completed at the time the first volunteer of this study was enrolled.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics of RO7049389 in Chinese HVs and evaluate potential ethnic differences between Chinese and non‐Asians.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In general, the safety profiles were comparable between non‐Asian and Chinese HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The higher exposure might be due to the liver uptake of RO7049389 by OATP1B.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus infection.     

Safety,tolerability, pharmacokinetic,and pharmacodynamic characteristics of vutiglabridin: A first‐in‐class,first‐in‐human study

This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A treatment with multifunctional effects is needed for obesity. Because the chronic inflammation caused by obesity plays an essential role in the progression of metabolic disorders, suppressing inflammatory pathways may be another important treatment goal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of vutiglabridin, a novel anti‐obesity agent, in healthy Korean and White individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Vutiglabridin was well‐tolerated in both Korean and White individuals. The pharmacokinetic parameters of vutiglabridin did not show dose‐proportionality, and after multiple administrations, vutiglabridin showed accumulation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides safety, pharmacokinetic, and pharmacodynamic information about vutiglabridin, which will be used for further trials for the treatment of obesity.     

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.     

Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study

The liver is the primary organ responsible for clearing most drugs from the body and thus determines systemic drug concentrations over time. Drug clearance by the liver appears to be directly related to organ size. In children, organ size changes as children age and grow. Liver volume has been correlated with body surface area (BSA) in healthy children and adults and has been estimated by functions of BSA. However, these relationships were derived from “typical” populations and it is unknown whether they extend to estimations of liver volumes for population “outliers,” such as children with overweight or obesity, who today represent one‐third of the pediatric population. Using computerized tomography or magnetic resonance imaging, this study measured liver volumes in 99 children (2–21 years) with normal weight, overweight, or obesity and compared organ measurements with estimates calculated using an established liver volume equation. A previously developed equation relating BSA to liver volume adequately estimates liver volumes in children, regardless of weight status.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​Liver anatomy and physiology are key determinants of hepatic drug metabolizing capacity captured by physiologically‐based pharmacokinetic (PBPK) models. Liver volumes in children with normal weight have been estimated as a function of body surface area (BSA), age, and other anthropometric features. These relationships have not been established for children with overweight or obesity, a growing patient population for whom PBPK modeling could provide valuable new pharmacology knowledge.

• WHAT QUESTION DID THIS STUDY ADDRESS?

​Are liver volumes in children with overweight or obesity accurately estimated by a previously published BSA‐based equation derived from children with normal weight?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

​This study demonstrates that liver volumes in children with overweight or obesity can be accurately estimated using BSA‐based equations previously established in children with normal weight, whereas estimations of liver volume as a function of other parameters, such as age, require corrections for weight status.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

​Accurate estimates of liver volume are critical scalars for predicting hepatic clearance with PBPK models, which are used to help approve and improve pharmaceutical therapies for children, 30% whom have overweight/obesity. The strong correlation of liver volumes with BSA across weight strata, paired with a weak correlation with body mass index z‐score, indicates that liver volume increases proportionally with overall body size (i.e., BSA) not obesity status per se. Our findings suggesting that separate obesity‐specific liver volume equations are not necessary for PBPK model development, as long as BSA is accounted for. ​     

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.     

No implication of HIV coinfection on the plasma exposure to rifampicin,pyrazinamide, and ethambutol in tuberculosis patients

There are contrasting findings regarding the effect of HIV on the pharmacokinetics of first‐line anti‐tubercular drugs (FLATDs) due to a lack of prospective controlled clinical studies, including patients with tuberculosis (TB) and patients with TB living with HIV. This study aims to assess the effect of HIV coinfection and antiviral therapy on the plasma exposure to FLATDs in patients with TB. HIV negative (TB‐HIV− group; n = 15) and HIV positive (TB‐HIV+ group; n = 18) adult patients with TB were enrolled during the second month of FLATDs treatment. All TB‐HIV+ patients were on treatment with lamivudine, tenofovir (or zidovudine), and raltegravir (or efavirenz). Serial blood sampling was collected over 24 h and FLATDs pharmacokinetic parameters were evaluated using noncompartmental methods. In the TB‐HIV+ patients, dose‐normalized plasma exposure area under the curve from zero to 24 h (nAUC_0–24; geometric mean and 95% confidence interval [CI]) values at steady‐state to rifampicin, pyrazinamide, and ethambutol were 18.38 (95% CI 13.74–24.59), 238.21 (95% CI 191.09–296.95), and 18.33 (95% CI 14.56–23.09) µg∙h/ml, respectively. Similar plasma exposure was found in the TB‐HIV− patients. The geometric mean and 90% CI of the ratios between TB‐HIV− and TB‐HIV+ groups suggest no significant pharmacokinetic interaction between the selected antivirals and FLATDs. Likewise, HIV coinfection itself does not appear to have any effect on the plasma exposure to FLATDs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

First‐line anti‐tubercular drugs (FLATDs) plasma exposure is an important variable of tuberculosis (TB) outcome; however, there are contrasting findings regarding the effect of HIV on the pharmacokinetics of FLATDs due to a lack of prospective controlled clinical studies, including HIV positive and HIV negative patients with TB.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluates the effect of HIV coinfection on the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients who are on stable therapy in the second month of FLATDs treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows no evidence that the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients with TB are affected by HIV coinfection or by any of the standard of care HIV comedications allowed in the study (lamivudine, zidovudine, tenofovir, efavirenz, or raltegravir).

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

HIV coinfection does not require dose adjustment of rifampicin, pyrazinamide, and ethambutol in patients with TB.     

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.     

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.     

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.     

Effects of sevelamer carbonate versus calcium acetate on vascular calcification,inflammation, and endothelial dysfunction in chronic kidney disease

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Non‐calcium‐based phosphate binders are effective in the patients with end stage kidney disease for lowering serum phosphorus and have demonstrated anti‐inflammatory effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study demonstrates a favorable reduction in systemic, vascular, and bone‐related inflammatory markers from treatment with sevelamer carbonate (SC) in the patients with chronic kidney disease (CKD) not on dialysis with normal serum phosphorus levels.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that patients with CKD not on dialysis may benefit from SC phosphate binders despite having a normal serum phosphorus level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study offers insight to the role phosphates binder may play in lowering inflammation and vascular calcification in patients with CKD not on dialysis.     

Pharmacogenetic variants and risk of remdesivir‐associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID‐19

Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir‐associated ALT elevations appear to be multifactorial, and further studies are needed.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Remdesivir is associated with liver injury in patients with coronavirus disease 2019 (COVID‐19), yet the mechanism of this injury is unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We utilized a genetically guided approach to investigate whether polymorphisms in drug metabolizing genes or transporters were associated with alanine aminotransferase (ALT) elevations following remdesivir treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE

Remdesivir was associated with a 30% increase in peak ALT in patients hospitalized with COVID‐19 which differs by population. Non‐Hispanic White (NHW) individuals with the CYP2C19 intermediate or poor metabolizer phenotype experienced a higher peak ALT than NHW individuals with normal, rapid, or ultrarapid metabolizer phenotype.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Pharmacogenetic approaches to investigation of severe adverse events may be useful in elucidating the mechanisms of drug metabolism and toxicity.     

Assessment of drug–drug interaction potential with EDP‐305, a farnesoid X receptor agonist,in healthy subjects

EDP‐305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP‐305 metabolism and that EDP‐305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug–drug interaction (DDI) potential of EDP‐305 co‐administered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP‐305. Results suggest caution when substrates of CYP3A4 are administered concomitantly with EDP‐305. A potential for increased exposure is apparent when CYP1A2 substrates with a narrow therapeutic index are administered with EDP‐305. In contrast, substrates of drug transporters can be administered concomitantly with EDP‐305 with a low potential for interactions. Coadministration of EDP‐305 and a combined OC had no relevant effects on plasma concentrations of the combined OC. Co‐administration of EDP‐305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. These results indicate low overall likelihood of interaction of EDP‐305 and other substrates through CYP mediated interactions. The interaction potential of EDP‐305 with drug transporters was low and of unlikely clinical significance. The EDP‐305 DDI profile allows for convenient administration in patients with NASH and other patient populations with comorbidities, with minimal dose modification of concomitant medications.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug metabolizing enzymes and transporters are implicated in clinically significant drug interactions. An important aspect for a new chemical entity is to establish the drug interaction potential early in the development process.

• WHAT QUESTION DID THIS STUDY ADDRESS?

EDP‐305 is a farnesoid X receptor agonist that is a potential treatment for nonalcoholic steatohepatitis and liver fibrosis. Based on preclinical studies, EDP‐305 had a low potential to inhibit cytochrome (CYP) isoenzymes. Four studies evaluated the potential of EDP‐305 with other drugs known to be substrates for drug metabolizing enzymes or transporters.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

These results indicate caution with co‐administration of EDP‐305 with drugs that are CYP3A4 and CYP1A2 substrates because of potentially clinically significant effects, and co‐administration of EDP‐305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. The drug–drug interaction potential of EDP‐305 with transporters or other agents was low and of unlikely clinical significance.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results from these four studies with EDP‐305 support the rationale for thorough investigation of potential clinically relevant drug interactions with new chemical entities.     

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.     

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.