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.     

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.     

Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.     

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.     

Model‐informed drug development for immuno‐oncology agonistic anti‐GITR antibody GWN323: Dose selection based on MABEL and biologically active dose

GWN323, an agonistic human anti‐GITR (glucocorticoid‐induced TNFR‐related protein) IgG1 antibody, was studied clinically as an immuno‐oncology therapeutic agent. A model‐based minimum anticipated biological effect level (MABEL) approach integrating in vitro and in vivo data informed dose selection for the first‐in‐human (FIH) study. Data evaluated included pharmacokinetics (PK) of DTA‐1.mIgG2a (mouse surrogate GITR antibody for GWN323), target‐engagement pharmacodynamic (PD) marker soluble GITR (sGITR), tumor shrinkage in Colon26 syngeneic mice administered with DTA‐1.mIgG2a, cytokine release of GWN323 in human peripheral blood mononuclear cells, and GITR binding affinity. A PK model was developed to describe DTA‐1.mIgG2a PK, and its relationship with sGITR was also modeled. Human GWN323 PK was predicted by allometric scaling of mouse PK. Based on the totality of PK/PD modeling and in vitro and in vivo pharmacology and toxicology data, MABEL was estimated to be 3–10 mg once every 3 weeks (Q3W), which informed the starting dose selection of the FIH study. Based on tumor kinetic PK/PD modeling of tumor inhibition by DTA‐1.mIgG2a in Colon26 mice and the predicted human PK of GWN323, the biologically active dose of GWN323 was predicted to be 350 mg Q3W, which informed the dose escalation of the FIH study. GWN323 PK from the FIH study was described by a population PK model; the relationship with ex vivo interleukin‐2 release, a target‐engagement marker, was also modeled. The clinical PK/PD modeling data supported the biological active dose projected from the translational PK/PD modeling in a “learn and confirm” paradigm of model‐informed drug development of GWN323.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Agonists of GITR have shown promising anti‐tumor activities in preclinical animal models by stimulating the activation and proliferation of effector memory T cells and decreasing regulatory T cell tumor infiltration. WHAT QUESTION DID THIS STUDY ADDRESS? This study features model‐based approach and translatability of preclinical in vitro and in vivo data to inform clinical study dose selection and study design for a GITR agonist antibody. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study utilized model‐informed approach to determine minimum anticipated biological effect level and predict biologically active dose in clinic. The approach integrated preclinical results from in vitro and in vivo models of anti‐tumor activities of GITR antibody to inform the design of a first‐in‐human (FIH) phase I study. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? A model‐informed drug development approach integrating pharmacokinetic/pharmacodynamic (PK/PD) modeling, in vitro and in vivo pharmacology, and preclinical toxicology data provided the scientific rationales and informed FIH dose selection for the immune agonistic GITR antibody GWN323, and was verified by clinical PK/PD modeling approach in a “learn and confirm” paradigm.     

CYP2S1 rs338599 polymorphism confers reduced risk to anti‐tuberculosis drug‐induced liver injury and may be a novel marker for its risk prediction

PurposeIn the present study, we would like to explore whether Cytochrome P450 2S1 (CYP2S1) rs338599 polymorphism confers risk to anti‐tuberculosis drug‐induced liver injury (ADLI) and provide evidence of being used as novel marker for ADLI risk prediction.Patients and methodsA total of 162 pulmonary tuberculosis patients admitted to Affiliated Hospital of Hebei University from August 2018 to March 2021 were selected. Patients who developed into ADLI were assigned as ADLI group (n = 50), and those who did not developed into ADLI were assigned as non‐ADLI group (n = 112). The CYP2S1 rs338599 polymorphism was detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method using binary logistic regression analyses through adjusting for age and sex.ResultsNo difference was detected in age, sex, smoking status, profession, education level, marital status, alcohol consumption, or using liver‐protecting drugs (p > 0.05). Compared with non‐ADLI group, GG genotype and G allele were significantly higher in ADLI group (p < 0.05).ConclusionOur results indicated that CYP2S1 rs338599 polymorphism conferred reduced risk to ADLI. The tuberculosis patients who had GG genotype or G allele were not susceptible to ADLI. CYP2S1 rs338599 polymorphism may be a novel marker for ADLI risk prediction.     

Short‐ and long‐term effects of body weight loss following calorie restriction and gastric bypass on CYP3A‐activity – a non‐randomized three‐armed controlled trial

It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet‐induced (n = 41) weight‐loss, and controls (n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (<1200 kcal/day) followed by a 6‐week very‐low‐energy‐diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight‐loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between‐group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A‐activity is not only dependent on weight‐loss through RYGB.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The current literature indicates an inverse relationship between body mass index (BMI) and CYP3A‐activity, and that systemic clearance of the CYP3A‐probe midazolam increases after Roux‐en‐Y gastric bypass (RYGB). However, the knowledge regarding changes in drug disposition following weight loss in general, and bariatric surgery in particular, is sparse and inconclusive, making drug dosing challenging. In addition, it remains uncertain whether pharmacokinetic changes following bariatric surgery are attributed to the gastrointestinal alterations per se and/or the subsequent weight loss.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Do body weight, weight loss, and RYGB impact CYP3A‐activity in vivo?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows that neither short‐term weight loss induced by RYGB or very‐low‐energy‐diet, nor RYGB per se, impact absolute bioavailability or systemic clearance of midazolam.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results suggests that dose adjustments of CYP3A substrate drugs, 30–50% of all drugs on the market, may not be necessary following nonsurgical and surgical weight loss neither in a short‐ nor long‐term perspective.     

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.     

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

N‐Nitrosamine (NA) impurities are considered genotoxic and have gained attention due to the recall of several marketed drug products associated with higher‐than‐permitted limits of these impurities. Rifampicin is an index inducer of multiple cytochrome P450s (CYPs) including CYP2B6, 2C8, 2C9, 2C19, and 3A4/5 and an inhibitor of OATP1B transporters (single dose). Hence, rifampicin is used extensively in clinical studies to assess drug–drug interactions (DDIs). Despite NA impurities being reported in rifampicin and rifapentine above the acceptable limits, these critical anti‐infective drugs are available for therapeutic use considering their benefit–risk profile. Reports of NA impurities in rifampicin products have created uncertainty around using rifampicin in clinical DDI studies, especially in healthy volunteers. Hence, a systematic investigation through a literature search was performed to determine possible alternative index inducer(s) to rifampicin. The available strong CYP3A inducers were selected from the University of Washington DDI Database and their in vivo DDI potential assessed using the data from clinical DDI studies with sensitive CYP3A substrates. To propose potential alternative CYP3A inducers, factors including lack of genotoxic potential, adequate safety, feasibility of multiple dose administration to healthy volunteers, and robust in vivo evidence of induction of CYP3A were considered. Based on the qualifying criteria, carbamazepine, phenytoin, and lumacaftor were identified to be the most promising alternatives to rifampicin for conducting CYP3A induction DDI studies. Strengths and limitations of the proposed alternative CYP3A inducers, the magnitude of in vivo CYP3A induction, appropriate study designs for each alternative inducer, and future perspectives are presented in this paper.     

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.     

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.     

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.     

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.     

Native right‐sided endocarditis in intravenous drug user: A case report

An increased rate of hospitalizations due to right‐sided infective endocarditis is currently witnessed due to the rapid rise of IV drug use. In this case report, we aim to discuss the long‐term outcome and highlight the various diagnostic approaches and management difficulties that are encountered in these cases.     

Erythropoiesis‐stimulating agents and incident malignancy in chronic kidney and end‐stage renal disease: A population‐based study

Research investigating incident malignancy risk in erythropoiesis‐stimulating agent (ESA) users with chronic kidney disease (CKD) is lacking. We aimed to compare the incident cancer risk between ESA and non‐ESA users with CKD or end‐stage renal disease (ESRD). In this retrospective cohort study, all adults newly diagnosed with CKD or ESRD between 2000 and 2012 were enrolled. The study population included 98,748 patients. After case–control matching, 7115 patients were included. The defined daily dose (DDD) of ESA was used as the unit for measuring the amount of ESA prescribed. The primary outcome was the risk of incident malignancy. The secondary outcomes were incident malignancy risk in different tertiles of cumulative ESA doses and the risk of different types of cancers. The risk of incident malignancy was 1.84 times higher with ESA treatment than without ESA treatment (hazard ratio, 1.84; 95% confidence interval, 1.43–2.36; p < 0.001). The malignancy risk was positively correlated with the cumulative dose of ESA (p‐for‐trend = 0.001) and a significant difference in the high annual cumulative DDD cohort (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.76–3.25; p < 0.001). The risk of genitourinary malignancy was 12.55 times higher with ESA treatment than without ESA treatment (HR, 12.55; 95% CI, 5.78–27.24; p < 0.001). ESA usage is associated with an increased risk of malignancy, particularly genitourinary cancers, in patients with CKD or ESRD. Clinicians should be aware of the occurrence of malignancy, and keep ESA dosage as low as possible.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Erythropoiesis‐stimulating agents (ESAs) are known to impact the outcomes of pre‐existing cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The de novo cancer risk for users of ESAs has not been fully examined. We aimed to compare the incident cancer risk between ESA and non‐ESA users with chronic kidney disease (CKD) or end‐stage renal disease (ESRD).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Users of erythropoiesis‐stimulating agents had 1.84 times increasing risk of overall de novo cancer, and a 12‐fold risk of genitourinary tract cancer. The risk of overall de novo cancer increased proportionally with the dosage of ESAs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Clinicians should more aggressively taper the dosage of ESAs while achieving the target hemoglobin level. Patients with CKD or ESRD treated with ESAs should be more alert to occurrence of malignancies, particularly genitourinary tract cancers.     

Urinary bladder cavernous hemangioma in a 3‐year‐old: A rare case report

Cavernous hemangioma (CH) of urinary bladder occurs relatively infrequently, accounting for 0.6% of all bladder tumors. This tumor may occur sporadically or coexist with other benign and malignant vascular lesions. In this report, we present a rare case of CH in a 3‐year‐old Ugandan girl. A 3‐year‐old girl was referred to Mbarara Regional Referral Hospital (MRRH) for urological evaluation following a 3‐year history of intravaginal swelling, dysuria, and heavy hematuria resulting in anemia. Imaging was consistent with polypoid bladder mass arising from the bladder trigone. Embryonal rhabdomyosarcoma was suspected based on clinical eyeballing. She was worked up for chemotherapy and received 26 cycles of vincristine sulfate, actinomycin‐d, and cyclophosphamide (VAC). Biopsy and fulguration were performed after optimizing the patient. Histopathology confirmed CH. The surgery was uneventful and resulted in complete cure. CH should be considered in the differential diagnosis of childhood genitourinary masses. It is a rare entity in the real‐life clinical practice and therefore can be overlooked. Excision biopsy and histology should be performed before initiating the patients to chemotherapy. CH is very insensitive to chemotherapy and therefore surgery maybe adequate in resource‐limited settings.     

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.     

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.