In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.

Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

BACKGROUND AND OBJECTIVE: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. METHODS: This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1-11, and (3) daily dose on days 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. RESULTS: For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. CONCLUSIONS: The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. GOV IDENTIFIER: NCT04577833.

Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer.

BACKGROUND AND OBJECTIVES: Two phase I studies assessed the drug-drug interaction potential of apalutamide as a substrate and perpetrator. METHODS: Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state. RESULTS: Systemic exposure (area under the plasma concentration-time curve) to single-dose apalutamide increased 68% with gemfibrozil but was relatively unchanged with itraconazole (study A). Apalutamide reduced systemic exposure to midazolam ↓92%, omeprazole ↓85%, S-warfarin ↓46%, fexofenadine ↓30%, rosuvastatin ↓41%, and pioglitazone ↓18% (study B). After a single dose, apalutamide is predominantly metabolized by CYP2C8, and less by CYP3A4. CONCLUSIONS: Co-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6.

Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 µg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.

Correction to: Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

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The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure.

PURPOSE: This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib's pharmacokinetics (PK) in healthy participants. METHODS: This open-label, sequential-design study included 20 healthy adults aged 18-55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3-6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib's PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model. RESULTS: AUC48h and AUClast of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1-116.3] and 92.5% [77.8-109.9], respectively); Cmax decreased by 62.5% (GMR [90% CI] 37.5% [26.4-53.4]), with delayed tmax (1-2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased Cmax on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study. CONCLUSIONS: The decrease in Cmax without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib's bioavailability. No dose adjustments are recommended during ibrutinib's co-administration with omeprazole or other pH-altering agents.

An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer.

PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.

A drug-drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies.

This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.