title: Population pharmacokinetic-pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade.
abstract: OBJECTIVE
  An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time.
  
  
  METHODS
  Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects.
  
  
  RESULTS
  Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg(-1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time.
  
  
  CONCLUSIONS
  Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.
authors.affiliation: Merck Sharp & Dohme Corp., Oss, The Netherlands. huubjan.kleijn@merck.com
authors.forename: Huub J
authors.initials: HJ
authors.lastname: Kleijn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Zollinger
authors.forename: Michiel W
authors.initials: MW
authors.lastname: van den Heuvel
authors.forename: Thomas
authors.initials: T
authors.lastname: Kerbusch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000732:Androstanols / Q000493:pharmacokinetics / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009126:Muscle Relaxation / Q000187:drug effects; D019148:Neuromuscular Blockade; D003473:Neuromuscular Nondepolarizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077123:Rocuronium; D000077122:Sugammadex; D055815:Young Adult; D047408:gamma-Cyclodextrins / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000732:Androstanols; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077123:Rocuronium