Strong CYP3A4 Inhibitor Research Articles

Physiologically-based pharmacokinetic modeling for optimal dosage prediction of olaparib when co-administered with CYP3A4 modulators and in patients with hepatic/renal impairment

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (Cmax) and trough concentration (Ctrough) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold Cmax (< 12,500 ng/mL) and Ctrough (772–2500 ng/mL). The population PBPK model for OLA was successfully developed and validated, demonstrating good consistency with clinically observed data. The ratios of predicted to observed values for Cmax and Ctrough fell within the range of 0.5 to 2.0. When OLA was co-administered with a strong or moderate CYP3A4 inhibitor, the recommended dosing regimens should be reduced to 100 mg BID and 150 mg BID, respectively. Additionally, the PBPK model also suggested that OLA could be not recommended with a strong or moderate CYP3A4 inducer. For patients with moderate hepatic and renal impairment, the dosing regimens of OLA were recommended to be reduced to 200 mg BID and 150 mg BID, respectively. In cases of severe hepatic and renal impairment, the PBPK model suggested a dosing regimen of 100 mg BID for OLA. Overall, this present PBPK model can determine the optimal dosing regimens for various clinical scenarios involving OLA.

Management of the interactions’ risks when using phytomedicines in children

phytomedicines play an essential role in the treatment of children's diseases. Means of&#x0D; plant origin have a better safety profile, and due to the content of biologically active substances, they af-fect various links of pathological processes. However, data on the safety and efficacy of phytomedicines&#x0D; in children are limited and mostly derived from studies in adults. In addition, there are risks of pharma-cokinetic and pharmacodynamic drug interactions. This study aims to study the risks of interaction when&#x0D; using phytomedicines and drugs in children. 100 parents participated in the study, most of whom had1 or 2 children. An analysis of the pharmacotherapy courses of 50 children was also done. It has beenestablished that parents when choosing medicines for children, consider their origin. Thus, more than70% of respondents consider phytomedicines to be safer for children and choose them for the treatmentof acute respiratory viral infections (73%), diseases of the throat (64%), oral cavity (59%), disorders ofthe gastrointestinal tract (28%) and others. The phytomedicines of choice were: Chlorophyllip, Sinupret,Wormil Phyto, Proteflazid, Darsil, Cholelesan, etc., which 80% of respondents used in combination withother medicinal products and without a doctor's prescription (75% of respondents). It was revealed that&#x0D; 10% of respondents noted the appearance of undesirable reactions after using phytomedicines, in com-bination with other medicinal products in children, the manifestations of which were: allergic reactions,&#x0D; digestive disorders, headache/dizziness. Based on the results of the analysis of the pharmacotherapycourses, it was established that the children received an average of 5.8 ± 1.7 medicines. In particular,28% received 2 or more phytomedicines. In more than 40% of children, the risks of pharmacokineticinteraction of phytomedicines with other medicinal products were revealed. Thus, 10% received herbal&#x0D; remedies based on St. John's wort, which is a CYP3A4 inducer and reduces the effectiveness of albenda-zole, omeprazole, pantoprazole, and levocetirizine. While more than 30% of children received products&#x0D; based on turmeric, silymarin, or grapefruit extract, which are strong CYP3A4 inhibitors. Risks of phar-macokinetic interaction at the stage of absorption (6% of children) were associated with the use of flax&#x0D; and plantain seeds. In 10% of children, the risk of pharmacodynamic interaction due to the use of thickeucalyptus leaf extract and an antiseptic agent was revealed. Therefore, when using phytomedicines in&#x0D; children, it is necessary to consider the risks of drug interactions. Phytomedicines can affect the pharmacokinetics of other drugs and change the realization of the clinical effect. When choosing and usingphytomedicines the interaction of the doctor-pharmacist-parent is essential.

Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study)

BackgroundPharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. MethodsThis cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. ResultsOf 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. ConclusionsBoosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.

Phase 1 study to evaluate the effects of rifampin or itraconazole on the pharmacokinetics of limertinib (ASK120067), a novel mutant-selective inhibitor of the epidermal growth factor receptor in healthy Chinese subjects

ABSTRACT Background Limertinib is a novel mutant-selective and irreversible inhibitor of the epidermal growth factor receptor under development. A phase 1 open, two-period, single-sequence, self-controlled, two-part study was initiated to characterize the effects of a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole) on the pharmacokinetics of limertinib. Research design and methods Twenty-four healthy subjects in each part received a single dose of limertinib alone (160 mg, Part A; 80 mg, Part B) and with multiple doses of rifampin 600 mg once daily (Part A) or itraconazole 200 mg twice daily (Part B). Results Coadministration of rifampin decreased exposure (area under the plasma concentration-time curve from time 0 to infinity, AUC0-inf) of limertinib and its active metabolite CCB4580030 by 87.86% (geometric least-squares mean [GLSM] ratio, 12.14%; 90% confidence interval [CI], 9.89–14.92) and 66.82% (GLSM ratio, 33.18%; 90% CI, 27.72–39.72), respectively. Coadministration of itraconazole increased the AUC0-inf of limertinib by 289.8% (GLSM ratio, 389.8%; 90% CI, 334.07–454.82), but decreased that of CCB4580030 by 35.96% (GLSM ratio, 64.04%; 90% CI, 50.78–80.77). Conclusions Our study demonstrates that the concomitant use of limertinib with strong CYP3A inducers or inhibitors is not recommended. A single dose of limertinib, administered with or without rifampin or itraconazole, is generally safe and well tolerated in healthy Chinese subjects. Clinical trial registration www.clinicaltrials.gov identifier is NCT05631678.

A comprehensive evaluation in clinic and physiologically-based pharmacokinetic modeling and simulation to confirm lack of cytochrome P450-mediated drug-drug interaction potential for pomotrelvir.

Pomotrelvir is a new chemical entity and potent direct-acting antiviral inhibitor of the main protease of coronaviruses. Here the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of pomotrelvir was evaluated for major CYP isoforms, starting with in vitro assays followed by the basic static model assessment. The identified CYP3A4-mediated potential DDIs were evaluated clinically at a supratherapeutic dose of 1050 mg twice daily (b.i.d.) of pomotrelvir, including pomotrelvir coadministration with ritonavir (strong inhibitor of CYP3A4) or midazolam (sensitive substrate of CYP3A4). Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed within the Simcyp Population-based Simulator using in vitro and in vivo information and validated with available human pharmacokinetic (PK) data. The PBPK model was simulated to assess the DDI potential for CYP isoforms that pomotrelvir has shown a weak to moderate DDI in vitro and for CYP3A4 at the therapeutic dose of 700 mg b.i.d. To support the use of pomotrelvir in women of childbearing potential, the impact of pomotrelvir on the exposure of the representative oral hormonal contraceptive drugs ethinyl estradiol and levonorgestrel was assessed using the PBPK model. The overall assessment suggested weak inhibition of pomotrelvir on CYP3A4 and minimal impact of a strong CYP3A4 inducer or inhibitor on pomotrelvir PK. Therefore, pomotrelvir is not anticipated to have clinically meaningful DDIs at the clinical dose. These comprehensive in vitro, in clinic, and in silico efforts indicate that the DDI potential of pomotrelvir is minimal, so excluding patients on concomitant medicines in clinical studies would not be required.

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model.

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1–21, itraconazole 100 mg twice daily from days 1–21, and azacytidine 100 mg subcutaneously, once daily from days 1–7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25–73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype.

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ). Following model verification, the PBPK model was used to explore the effects of strong CYP3A4 and CYP2C19 inducers, and strong, moderate, and weak CYP2C19 and CYP3A4 inhibitors on mavacamten pharmacokinetics (PK) in a healthy population, with the effect of CYP2C19 phenotype predicted for poor, intermediate, normal, and ultrarapid metabolizers. The PBPK model met the acceptance criteria for all verification simulations (> 80% of model-predicted PK parameters within 2-fold of those observed clinically). A weak induction effect was predicted when mavacamten was administered with a strong CYP3A4 inducer in poor metabolizers. Moderate reductions in mavacamten exposure were predicted with a strong CYP2C19/CYP3A4 inducer in all CYP2C19 phenotypes. Except for the effect of strong CYP2C19 inhibitors on ultrarapid metabolizers, steady-state area under plasma concentration-time curve and maximum plasma concentration values were weakly affected (< 2-fold) or not affected (< 1.25-fold), regardless of CYP2C19 phenotype. In conclusion, a fit-for-purpose PBPK model was developed and verified, which accurately predicted the available clinical data and was used to simulate the potential impact of CYP induction and inhibition on mavacamten PKs, stratified by CYP2C19 phenotype.

Effects of CYP3A4 inhibition/inductionand OATP inhibition on the pharmacokinetics of atogepant in healthy adults.

Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: Cmax and AUC of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer.

Brentuximab vedotin with AVD for stage II–IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial

Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per μL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. National Institutes of Health and National Cancer Institute.

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (<1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers. In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics. The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity(AUC0-inf) by104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%. Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

Futibatinib (Lytgobi®)

Futibatinib (Lytgobi®)

Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia.

e19011 Background: Safer and more effective lower-intensity treatment (Tx) options are needed for patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of VEN, an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible pts with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral-AZA allows for extended dosing schedules vs. Inj AZA. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in pts with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible pts are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The Oral-AZA starting dose is 300 mg QD × 14 days (d) per 28d cycle (dose level [DL] −1), which can be de-escalated to 200 mg QD × 14d depending on dose-limiting toxicities (DLTs); VEN 400 mg QD is taken continuously (or 21d per cycle; DL −2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Pt enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 pts (3 female; aged 51–80 years). 3 pts had 1 prior line of Tx and 2 pts had 2. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 pts, 3 reported ≥ 1 any grade (Gr) drug-related adverse event, the most common of which were Gr 1–3 diarrhea (2 pts) and Gr 1–2 nausea (2 pts). Gr 3 febrile neutropenia, which was not deemed drug related, was reported in 4 pts (6 episodes total). In 1 pt, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to Gr 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-Tx with a strong CYP3A inhibitor (per protocol). 3 pts died after Tx discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 pts remained on Tx and best response achieved was CRi in 2 pts and stable disease in 3 pts. Conclusions: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the 2 agents. Further evaluation in AML is warranted. Clinical trial information: NCT04887857 .

Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis.

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2 and 3 Clinical Trials.

Following the decade long clinical investigation, venetoclax has accrued PK data across multiple populations and widely-ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population pharmacokinetic (popPK) modeling. Plasma concentration-time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from nine indications and healthy volunteers. A nonlinear mixed-effect model was developed. Covariates were evaluated with full covariate modeling approach. A two-compartment model with three transit absorption compartments described the data well. The impact of moderate and strong CYP3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution (V2/F), food effect on relative bioavailability (F1) and dose non-linearity was confirmed. Newly identified covariate effects include 48% lower CL/F in severe hepatic impairment subjects, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least one strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross-indication popPK model with improved absorption phase characterization was developed. Covariate analyses suggested lower CL/F for severe hepatic impairment subjects and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor. This article is protected by copyright. All rights reserved.

Prevalence and bleeding risk associated with the concomitant use of direct oral anticoagulants and antiarrhythmic drugs in patients with atrial fibrillation, based on the French healthcare insurance database.

Pharmacokinetic interactions exist between apixaban or rivaroxaban, and CYP3A4 and P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem. We aimed to estimate the prevalence of exposure to this drug-drug association (DDA) and to assess the bleeding risk associated in patients with atrial fibrillation (AF). We conducted a cohort study using a representative 1/97th sample of the French healthcare insurance database between 2014 and 2019. Patients with AF receiving apixaban or rivaroxaban were included and followed-up until hospitalization for bleeding, death, discontinuation of apixaban or rivaroxaban, exposure to strong CYP3A4 inhibitor, or until December 31st 2019, whichever came first. Primary outcome was hospitalization for bleeding registered as primary diagnosis. The association between the exposure to the DDA and hospitalization for bleeding was evaluated as a time-dependent variable in Cox model. Between 2014 and 2019, the AF population under apixaban or rivaroxaban represented 10,392 patients. During the study period, the annual average prevalence of DDA exposure in this population was 38.9%. Among the 10,392 patients, 223 (2.1%) were hospitalized for bleeding, of which 75 (33.6%) received the association and 148 (66.4%) received apixaban or rivaroxaban alone. There was no association between DDA exposure and risk of hospitalization for bleeding (aHR = 1.19, [95% CI: 0.90, 1.58]). Age (HR 1.03 [1.02, 1.05]) and male gender (HR 1.72 [1.28, 2.30]) were associated with an increased risk of hospitalization for bleeding. Exposure to antiarrhythmic drugs was not associated with an increased risk of hospitalization for bleeding in patients with AF under rivaroxaban or apixaban.

Itraconazole interferes in the pharmacokinetics of fuzuloparib in healthy volunteers.

Fuzuloparib is an orally administered poly [ADP-ribose] polymerase 1 (PARP1) inhibitor and has potential anti-tumor effect on ovarian cancer (such as fallopian tube cancer and primary peritoneal cancer) in China. As fuzuloparib is metabolized mainly by CYP3A4, we explored the effect of itraconazole, a strong CYP3A4 inhibitor, on a single oral dose of fuzuloparib in healthy male subjects. An open-label, single-arm, fixed sequence study was conducted. Twenty healthy adult males received one single dose of fuzuloparib (20mg) with one dose administered alone and the other dose coadministered with itraconazole. Subjects received 200mg QD itraconazole for 6days during the study. Serials of blood samples were collected pre-dose of each fuzuloparib capsule administration and 48h post-dose, and were used to analyze the PK parameters of fuzuloparib. Coadministration of repeated 200mg QD oral doses of itraconazole for 6days increased fuzuloparib exposure by 1.51-fold and 4.81-fold for peak plasma concentration and area under the plasma concentration-time curve (AUC), respectively. Oral administration of 20mg fuzuloparib alone or together with itraconazole was safe and tolerable in healthy male subjects. The CYP3A4 inhibitor itraconazole has a significant influence on the PK behavior of fuzuloparib, suggesting to avoid using strong CYP3A4 inhibitors simultaneously with fuzuloparib. If it is necessary to use a strong CYP3A4 inhibitor, fuzuloparib would be discontinued and be restored to the original dose and frequency of administration after 5-7 half lives of CYP3A4 inhibitor stopped. http://www.chinadrugtrials.org.cn/index.html , CTR20191271.