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

详细信息    查看全文

• 作者：Luc Dirix ; MD ; PhD¹ ; ^{luc.dirix@telenet.be" class="auth_mail" title="E-mail the corresponding author} ; Helen Swaisland² ; ^* ; Henk M.W. Verheul ; MD ; PhD³ ; Sylvie Rottey ; MD ; PhD⁴ ; Karin Leunen ; MD⁵ ; Guy Jerusalem ; MD ; PhD⁶ ; Christian Rolfo ; MD ; PhD⁷ ; Dorte Nielsen ; MD ; DMSc⁸ ; L. Rhoda Molife ; BMedSci ; BM BS ; MRCP ; MD ; MSc⁹ ; Rebecca Kristeleit ; BSc ; MRCP ; PhD¹⁰ ; Judith de Vos-Geelen ; MD ; PhD¹¹ ; Morten Mau-Sø ; rensen ; MD ; PhD¹² ; Patricia Soetekouw ; MD¹¹ ; Carla van Herpen ; MD ; PhD¹³ ; Anitra Fielding ; MBChB² ; Karen So ; MBBS ; MRCS ; MD¹⁴ ; Wendy Bannister¹⁵ ; Ruth Plummer ; MD ; D.Phil ; FRCP¹⁶
• 关键词：CYP3A4 ; itraconazole ; olaparib ; pharmacokinetic ; rifampin
• 刊名：Clinical Therapeutics
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：38
• 期：10
• 页码：2286-2299
• 全文大小：350 K

文摘

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

Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC_0–t and C_max fell within the bioequivalence range of 0.80–1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or C_max in the presence of rifampin compared with olaparib alone).

Findings

In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: C_max treatment ratio, 1.42 (90% CI, 1.33–1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44–2.97). Mean CL/F and V_z/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t_½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: C_max treatment ratio, 0.29 (90% CI, 0.24–0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11–0.16). CL/F and V_z/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t_½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile.

Implications

Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment.

ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).