A 1-step Bayesian predictive approach for evaluating in vitro in vivo correlation (IVIVC).
IVIVC (in vitro in vivo correlation) methods may support approving a change in formulation of a drug using only in vitro dissolution data without additional bioequivalence trials in human subjects. Most current IVIVC methods express the in vivo plasma concentration of a drug formulation as a function of the cumulative in vivo absorption. The absorption is not directly observable, so is estimated by the cumulative dissolution of the drug formulation in in vitro dissolution trials. The calculations conventionally entail the complex and potentially unstable mathematical operations of convolution and deconvolution, or approximations aimed at omitting their need. This paper describes, and illustrates with data on a controlled-release formulation, a Bayesian approach to evaluating IVIVC that does not require convolution, deconvolution or approximation. This approach incorporates between- and within-subject (or replicate) variability without assuming asymptotic normality. The plasma concentration curve is expressed in terms of the in vitro dissolution percentage instead of time, recognizing that this correspondence may be noisy because of the various sources of error. All conventional functions of the concentration curve such as AUC, C(max) and T(max) can be expressed in terms of dissolution percentage, with uncertainties arising from variability in measuring absorption and dissolution accounted for explicitly.
Gould
A Lawrence
AL
Merck Research Laboratories, North Wales, PA 19454, USA. goulda@merck.com
Agrawal
Nancy G B
NG
Goel
Thanh V
TV
Fitzpatrick
Shaun
S
D000042:Absorption; D000284:Administration, Oral; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000706:statistics & numerical data*; D019295:Computational Biology / Q000379:methods; D005079:Excipients / Q000493:pharmacokinetics; D006801:Humans; D008433:Mathematics; D012995:Solubility; D013223:Statistics as Topic; D013810:Therapeutic Equivalency
D005079:Excipients