Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib

Abstract

Background Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir. Methods In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies. Results Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μg*h/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μg*h/mL (CV:116%, p = 0.545), 1.68 μg/mL (CV:68%, p = 0.500) and 1.06 μg/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported. Conclusions Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.

Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

“…In an open-label, crossover study, investigators compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (control arm) with erlotinib 75 mg daily plus ritonavir 200 mg daily (intervention arm). 51 The authors concluded that the pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with ritonavir was similar to 150 mg erlotinib. In fact, the authors concluded that ritonavir boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP 3A4.…”

Off-label, but on target: the evidence needed to implement alternative dosing regimens of anticancer drugs

“… 18 , 19 , 35 , 36 , 37 Recently similar pharmacokinetic exposure was shown for a reduced dose of erlotinib with the cytochrome P450 (CYP)3A inhibitor ritonavir compared with the standard erlotinib dose. 18 Several studies are currently ongoing in which the lower equivalent dose of olaparib in combination with the CYP3A inhibitor cobicistat is explored (NCT05078671) and in which ritonavir is used to facilitate the oral administration of docetaxel by increasing bioavailability to reach exposure levels comparable to the intravenous formulation (NCT04028388). A challenge that needs to be acknowledged when pharmacokinetic boosting is the potential interaction with other drugs in the heavily cotreated oncology patient population.…”

Atazanavir/Ritonavir Increased Tizoxanide Exposure from Oral Nitazoxanide through Pharmacokinetic Interaction in Healthy Volunteers

“…Precedent exists for concomitant administration of a drug with another agent that inhibits or induces certain aspect(s) of its disposition pathway to improve systemic exposure, a strategy known as pharmacokinetic boosting. This has been applied to drugs used in the treatment of different diseases such as HIV and cancer [26][27][28][29][30]. Interaction between nitazoxanide and atazanavir/ritonavir has not been reported.…”