title: Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology.
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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Novartis Pharmaceuticals Corporation.
authors: Department of Medical Oncology, Hôpital Saint André, Bordeaux, France.
authors: Alain
authors: A
authors: Ravaud
authors: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
authors: Shweta R
authors: SR
authors: Urva
authors: Oncology Biometrics and Data Management, Novartis Pharma AG, Basel, Switzerland.
authors: Kai
authors: K
authors: Grosch
authors: Oncology Clinical Pharmacology, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
authors: Wing K
authors: WK
authors: Cheung
authors: Oncology Clinical Development, Novartis Pharma AG, Basel, Switzerland.
authors: Oezlem
authors: O
authors: Anak
authors: Oncology Clinical Development, Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA. Electronic address: dalila.sellami@novartis.com.
authors: Dalila B
authors: DB
authors: Sellami
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D018572:Disease-Free Survival; D000068338:Everolimus; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D000068338:Everolimus; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus
keywords: Cancer; Efficacy; Everolimus; Pharmacokinetics; Safety