Examining the Use of a Mechanistic Model to Generate an In Vivo/In Vitro Correlation: Journey Through a Thought Process.
The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol.
Office of New Drug Evaluation, Center for Veterinary Medicine, US FDA, Rockville, Maryland, 20855, USA.
Bipin
B
Mistry
Simcyp (a Certera company), Blades Enterprise Centre, Sheffield, UK.
Nikunjkumar
N
Patel
Simcyp (a Certera company), Blades Enterprise Centre, Sheffield, UK.
Masoud
M
Jamei
Simcyp (a Certera company), Blades Enterprise Centre, Sheffield, UK.|Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Stopford Building, Manchester, UK.
Amin
A
Rostami-Hodjegan
Office of New Drug Evaluation, Center for Veterinary Medicine, US FDA, Rockville, Maryland, 20855, USA. marilyn.martinez@fda.hhs.gov.
Marilyn N
MN
Martinez
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000378:metabolism*; D008875:Middle Aged; D008962:Models, Theoretical; D055815:Young Adult
D003692:Delayed-Action Preparations; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol
in vivo/in vitro correlation; mechanistic model; metoprolol