Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies

Abstract

Purpose: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. Methods

Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

“…Figure a shows the mean concentration–time profile in plasma simulated by the PBPK tablet model for a single tablet dose of olaparib (300 mg) in the fasted state, accounting for CYP3A and P‐gp inhibition and induction parameters; Figure b shows that for multiple tablet doses. The predicted PK parameters (AUC and C max ) were within 1.5‐fold of the PK parameters observed for olaparib tablet monotherapy in the clinical trials following single or multiple oral tablet doses ( Table ) . For multiple tablet dosing, there was a predicted ∼24% decrease in olaparib clearance and therefore an increase in AUC at steady state (AUC ss ) of 1.35‐fold over day 1 predicted AUC; this was in agreement with observed clinical data (NCT01921140) .…”

“…Olaparib tablet and capsule simulations are shown in Figure S2 Briefly, olaparib tablet/capsule exposure was simulated in the presence and absence of multiple doses of the CYP3A4 inhibitors itraconazole (200 mg replicating NCT01900028 (tablet study)), fluconazole (200 mg), and fluvoxamine (50 mg) and CYP3A4 inducers rifampicin (600 mg replicating NCT01929603 (tablet study)), efavirenz (600 mg), and dexamethasone (8 mg). Exposures of the CYP3A substrates midazolam (5 mg) and simvastatin (40 mg), and the P‐gp substrate digoxin (0.5 mg and 0.25 mg with olaparib tablet and capsule formulations, respectively) and UGT1A1 substrate raltegravir (400 mg) were simulated following a single dose in the presence and absence of daily dosing of olaparib tablets/capsules.…”

“…20 The DDI potential of olaparib is therefore multivariate, and predicting the net effect on CYP3A in vivo is challenging. The DDI of olaparib tablet with a CYP3A inhibitor (itraconazole) and inducer (rifampicin) has been studied in clinical trials of patients with solid tumors 21 ; however, equivalent studies have not been performed with the capsule. In vitro data have also indicated that olaparib shows inhibition of P-glycoprotein (P-gp) and UGT1A1 with measured IC 50 values of 76 and 96.7 lM, respectively.…”

“…The objectives of the studies reported here were to: Develop a mechanistic PBPK model of olaparib tablet and capsule formulations using Simcyp (Sheffield, UK) with olaparib (capsule and tablet) physiological parameters, human in vitro data, and human in vivo data to simulate olaparib exposure. Utilize observed clinical data to verify model predictions of the effect of coadministration of olaparib with a CYP3A4 inhibitor (itraconazole) or inducer (rifampicin). Bridge the DDI outcome of the tablet to the capsule to provide dose‐adjustment information for the approved capsule formulation by predicting the effect of weak to potent CYP3A inhibitors and inducers on exposure to olaparib capsule using the PBPK model. In addition, provide dose‐adjustment recommendations for the tablet formulation given with weak to moderate CYP3A inhibitors or inducers. Simulate the DDI risk of olaparib as a perpetrator drug using the probe CYP3A substrates midazolam and simvastatin, the P‐gp substrate digoxin, and the UGT1A1 substrate raltegravir. Utilize the PBPK models developed based on single‐dose olaparib clinical trial DDIs to simulate DDI outcomes following multiple‐dose administration. Apply clinical data from olaparib tablet studies in patients with mild/moderate renal or hepatic impairment to the PBPK models to predict changes in olaparib exposure when given to patients with mild, moderate, or severe renal or hepatic impairment after multiple dosing. Use the PBPK models to predict olaparib exposure in pediatric patients to recommend dosing regimens for clinical pediatric studies. …”

A Novel Use of Olaparib for the Treatment of Metastatic Castration‐Recurrent Prostate Cancer

“…Olaparib also interacts with strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, and St. John's wort) . Rifampin significantly decreased olaparib's bioavailability by 87% . If a strong or moderate CYP3A inducer must be administered, olaparib's efficacy may be decreased .…”