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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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

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

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

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

• WHAT QUESTION DID THIS STUDY ADDRESS?

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

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

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

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

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

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.     

Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

Bavachinin, a natural bioactive flavanone, is reported to have many pharmacological proprieties, especially anti-osteoporosis activity. Here we aim to determine the roles of cytochrome P450s (CYP), UDP-glucuronosyltransferases (UGT), and efflux transporters in metabolism and drug–drug interactions (DDI) of bavachinin. Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM) and human intestine microsomes (HIM). Reaction phenotyping was used to identify the main CYPs and UGTs. Gene silencing methods were employed to investigate the roles of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa1A1 cells. Inhibition mechanisms towards CYPs and UGTs were explored through kinetic modeling. Three phase I metabolites (M1–M3) and one glucuronide (G1) were detected after incubation of bavachinin with HLM and HIM. The intrinsic clearance (CL_int) values of M1 and G1 by HLM were 89.4 and 270.2 μL min⁻¹ mg⁻¹, respectively, while those of M3 and G1 by HIM were 25.8 and 247.1 μL min⁻¹ mg⁻¹, respectively. CYP1A1, 1A2, 1B1, 2C8, 2C19, and UGT1A1, 1A8 participated more in bavachinin metabolism. The metabolism showed marked species difference. BCRP and MRP4 were identified as the main contributors. Bavachinin displayed potent inhibitory effects against several CYP and UGT isozymes (K_i = 0.28–2.53 μM). Bavachinin was subjected to undergo metabolism and disposition by CYPs, UGTs, BCRP, MRP4, and was also a potent non-selective inhibitor against several CYPs and UGTs.

Metabolism, efflux transport and drug–drug interactions of bavachinin.     

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.     

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.     

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 novel drug–drug coamorphous system without molecular interactions: improve the physicochemical properties of tadalafil and repaglinide

Tadalafil and repaglinide, categorized as BCS class II drugs, have low oral bioavailabilities due to their poorly aqueous solubilities and dissolutions. The aim of this study was to enhance the dissolution of tadalafil and repaglinide by co-amorphization technology and evaluate the storage and compression stability of such coamorphous system. Based on Flory–Huggins interaction parameter (χ ≤ 0) and Hansen solubility parameter (δ_t ≤ 7 MPa^0.5) calculations, tadalafil and repaglinide was predicted to be well miscible with each other. Coamorphous tadalafil–repaglinide (molar ratio, 1 : 1) was prepared by solvent-evaporation method and characterized with respect to its thermal properties, possible molecular interactions. A single T_g (73.1 °C) observed in DSC and disappearance of crystallinity in PXRD indicated the formation of coamorphous system. Principal component analysis of FTIR in combination with Raman spectroscopy and Ss ¹³C NMR suggested the absence of intermolecular interactions in coamorphous tadalafil–repaglinide. In comparison to pure crystalline forms and their physical mixtures, both drugs in coamorphous system exhibited significant increases in intrinsic dissolution rate (1.5–3-fold) and could maintain supersaturated level for at least 4 hours in non-sink dissolution. In addition, the coamorphous tadalafil–repaglinide showed improved stability compared to the pure amorphous forms under long-term stability and accelerated storage conditions as well as under high compressing pressure. In conclusion, this study showed that co-amorphization technique is a promising approach for improving the dissolution rate of poorly water-soluble drugs and for stabilizing amorphous drugs.

The coamorphous tadalafil–repaglinide (molar ratio, 1 : 1) prepared by solvent-evaporation method significantly improve the physicochemical properties of tadalafil and repaglinide.     

A target‐mediated drug disposition population pharmacokinetic model of GC1118, a novel anti‐EGFR antibody,in patients with solid tumors

AbstractGC1118 is a monoclonal antibody for epidermal growth factor receptor (EGFR) that is currently under clinical development to treat patients with solid tumors. In this study, the pharmacokinetics (PKs) of GC1118 were modeled in solid tumor patients who received a 2‐h intravenous infusion of GC1118 at 0.3, 1, 3, 5, or 4 mg/kg once‐weekly (Q1W) on days 1, 8, 15, and 22 or 8 mg/kg every other week on days 1 and 15. A target‐mediated drug disposition population PK model adequately described the concentration‐time profiles of GC1118. Monte‐Carlo simulation experiments of the PK profiles and EGFR occupancies (ROs) by GC1118 based on the final model showed that Q1W at 4 or 5 mg/kg will produce a better antitumor effect than Q2W at 8 mg/kg. Because GC1118 was safer at 4 mg/kg than 5 mg/kg in the phase I study, we suggest to test the 4 mg/kg Q1W regimen in further clinical trials with GC1118. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GC1118, a fully human IgG₁ monoclonal antibody (mAb) for epidermal growth factor receptor (EGFR), showed a nonlinear pharmacokinetic (PK) profile in monkeys and humans. The total clearance of GC1118 decreased as the dose was increased up to 3–4 mg/kg in humans, beyond which it remained stable. The recommended phase II dose for GC1118 was 4 mg/kg intravenously infused over 2 h once weekly.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We developed a target‐mediated drug disposition (TMDD) population PK model that described the nonlinear PK profile of GC1118 in patients with solid tumors. We also simulated the PK profiles and receptor occupancies for different dosage regimens.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The TMDD population PK model adequately described the nonlinear and multiphasic PK profiles of GC1118 in humans. The simulation experiment showed that once‐weekly GC1118 at 4–5 mg/kg could be more efficacious than the biweekly regimen at 8 mg/kg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The pharmacometrics analysis could support better informed drug development decisions for GC1118, particularly for determining an optimal dosage regimen.     

The pH-triggered drug release and simultaneous carrier decomposition of effervescent SiO2–drug–Na2CO3 composite nanoparticles: to improve the antitumor activity of hydrophobic drugs

To achieve a better release effect of hydrophobic drugs and spontaneous nanocarrier disintegration by dissolution as well as the CO₂ production of Na₂CO₃ further, improving the therapeutic effect of hydrophobic drugs, and thereby avoiding the accumulation of the nanocarrier in vivo to produce organ toxicity, effervescent SiO₂–drug–Na₂CO₃ composite nanoparticles (ESNs) were prepared in this study using a tetraethyl orthosilicate hydrolysis method. Sodium carbonate was used as the effervescent disintegrant to respond to the acidic microenvironment of the tumor. The properties of ESNs were assessed and TEM images were taken to verify the self-disintegration characteristics of nanocarrier materials. The in vitro anticancer efficacy of ESNs was evaluated in human breast cancer MCF-7 cells. ESNs loaded with hydrophobic drugs were successfully constructed, and showed high entrapment efficiency and drug loading. The nanocarrier successfully achieved self-disintegration in a PBS environment of pH value at 5.0, and showed excellent antitumor effect in vitro. ESNs can effectively load hydrophobic drugs and achieve self-disintegration, while avoiding toxicity from the accumulation of the nanocarrier. These results suggest that ESNs are a promising drug delivery system capable of maximizing the anticancer therapeutic efficacy and minimizing the systemic toxicity.

Effervescent SiO₂–drug–Na₂CO₃ composite nanoparticles were prepared in this study using a tetraethyl orthosilicate hydrolysis method to achieve a better release effect of hydrophobic drugs and spontaneous nanocarrier disintegration by dissolution.     

Evaluation of the potential drug interactions mediated through P‐gp,OCT2, and MATE1/2K with filgotinib in healthy subjects

Filgotinib, a preferential Janus Kinase‐1 inhibitor, is approved in Europe and Japan for treatment of rheumatoid arthritis and is being developed for treatment of other chronic inflammatory diseases. Three drug‐drug interactions studies were conducted in healthy subjects to evaluate the effect of P‐glycoprotein (P‐gp) modulation (study 1: P‐gp inhibition by itraconazole and study 2: P‐gp induction by rifampin) on filgotinib pharmacokinetics and the potential of filgotinib to impact exposure of metformin, an organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2K substrate (study 3). Co‐administration of filgotinib with itraconazole increased filgotinib exposure (maximum concentration [C _max] by 64% and area under the curve to infinity [AUC_inf] by 45%) but had no effect on the exposure of GS‐829845, filgotinib’s primary metabolite. Rifampin moderately reduced exposures of filgotinib and GS‐829845 (C _max by 26% and AUC_inf by 27% for filgotinib; C _max by 19% and AUC_inf by 38% for GS‐829845). The data confirmed that filgotinib is a P‐gp substrate. However, the magnitude of change in filgotinib/GS‐829845 exposure by P‐gp modulators is not deemed to be clinically relevant based on filgotinib exposure‐response analyses in subjects with rheumatoid arthritis. Filgotinib did not alter metformin exposures, indicating that filgotinib and GS‐829845 do not inhibit OCT2 and MATE1/2K at the clinical doses. Filgotinib was generally well‐tolerated when administered alone or with the co‐administered drugs in the studies. Results from these studies were the basis to enable the use of P‐gp modulators and substrates of OCT2, MATE1, and MATE2K with filgotinib without the need for dose modifications in the current approved rheumatoid arthritis population.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Filgotinib is approved for treatment of patients with rheumatoid arthritis in Europe and Japan. Polypharmacy is common in patients with inflammatory diseases, such as rheumatoid arthritis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the drug‐drug interaction potential for filgotinib with P‐gp modulators or substrates of OCT2, MATE1, and MATE2K to inform on the dosing recommendations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Filgotinib and GS‐829845 exposures are not impacted by P‐gp inhibitors or inducers to any clinically relevant extent. Additionally, filgotinib and GS‐829845 are not inhibitors of OCT2, MATE1, and MATE2K at the clinically relevant exposures.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Concomitant use of P‐gp modulators or substrates of OCT2, MATE1, and MATE2K with filgotinib does not require dose modifications.     

Immune‐mediated thrombotic thrombocytopenic purpura in a Jehovah’s Witness – Effectiveness of incorporating extracorporeal immunoadsorption to caplacizumab,steroids and rituximab

We report the case of a Jehovah''s Witness adolescent patient with immune‐mediated thrombotic thrombocytopenic purpura after SARS‐Cov2 infection successfully treated without therapeutic plasma exchange (TPE) using caplacizumab, corticosteroids, rituximab, and extracorporeal immunoadsorption (EIA). Further patients for whom TPE is not an option might benefit from this approach.     

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.