Alain Ravaud1, Shweta R Urva2, Kai Grosch3, Wing K Cheung2, Oezlem Anak4, Dalila B Sellami5. 1. Department of Medical Oncology, Hôpital Saint André, Bordeaux, France. 2. Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA. 3. Oncology Biometrics and Data Management, Novartis Pharma AG, Basel, Switzerland. 4. Oncology Clinical Development, Novartis Pharma AG, Basel, Switzerland. 5. Oncology Clinical Development, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA. Electronic address: dalila.sellami@novartis.com.
Abstract
BACKGROUND: In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin). METHODS: Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled. FINDINGS: Efficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23-1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69-1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12-3.34), stomatitis (RR 1.49, 95% CI 1.05-2.10) and metabolic (RR 1.30, 95% CI 1.02-1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%. INTERPRETATION: A 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events. FUNDING: Novartis Pharmaceuticals Corporation.
BACKGROUND: In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin). METHODS: Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled. FINDINGS: Efficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23-1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69-1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12-3.34), stomatitis (RR 1.49, 95% CI 1.05-2.10) and metabolic (RR 1.30, 95% CI 1.02-1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%. INTERPRETATION: A 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events. FUNDING: Novartis Pharmaceuticals Corporation.
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