Analyzing the Potential Root Causes of Variability of Pharmacokinetics in Preclinical Species.
The purpose of this research was to assess variability in pharmacokinetic profiles (PK variability) in preclinical species and identify the risk factors associated with the properties of a drug molecule that contribute to the variability. Exposure data in mouse, rat, dog, and monkey for a total of 16,592 research compounds studied between 1999 and 2013 were included in the analysis. Both in vivo study parameters and in silico/experimental physicochemical properties of the molecules were analyzed. Areas under the plasma concentration vs time curves (AUC) were used to assess PK variability. PK variability was calculated as the ratio of the highest AUC within a defined set of AUC values (AUCmax) over the lowest AUC within that set (AUCmin). Both intra- and inter-animal variability were analyzed, with intra-animal exposures found to be more variable than inter-animal exposures. While several routes of administration were initially studied, the analysis was focused on the oral route, which corresponds to the large majority of data points and displays higher variability than the subcutaneous, intraperitoneal, or intravenous routes. The association between inter-animal PK variability and physical properties was studied, and low solubility, high administered dose, high preclinical dose number (PDo), and pH-dependent solubility were found to be associated with high variability in exposures. Permeability-as assessed by the measured permeability coefficient in the LLC-PK1 cell line-was also considered but appeared to only have a weak association with variability. Consistent with these findings, BCS class I and III compounds were found to be less prone to PK variability than BCS class II and IV compounds. A modest association of PK variability with clearance was observed while the association with bioavailability, a higher PK variability for compounds with lower bioavailability, appeared to be more pronounced. Finally, two case studies that highlight PK variability issues are described, and successful mitigation strategies are presented.
Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc. , Boston, Massachusetts 02115, United States.
Pierre
P
Daublain
Discovery Pharmaceutical Sciences, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Kung-I
0000-0002-4470-4363
KI
Feng
Chemistry Modeling and Informatics, MRL, Merck & Co., Inc. , Boston, Massachusetts 02115, United States.
Michael D
MD
Altman
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MRL, Merck & Co., Inc. , Boston, Massachusetts 02115, United States.
Iain
I
Martin
Biochemical Toxicology and Toxicokinetics, MRL, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
Suman
S
Mukherjee
Biopharmaceutics & Specialty Dosage Forms, MRL, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
Rebecca
R
Nofsinger
Medicinal Chemistry, MRL, Merck & Co., Inc. , Boston, Massachusetts 02115, United States.
Alan B
AB
Northrup
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Richard
R
Tschirret-Guth
Drug Safety, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033 United States.
Mark
M
Cartwright
Analytical Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
Caroline
C
McGregor
D000818:Animals; D019540:Area Under Curve; D001826:Body Fluids / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology; D018374:LLC-PK1 Cells; D051379:Mice; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D051381:Rats; D013552:Swine
D004364:Pharmaceutical Preparations
AUC; FaSSIF; SGF; exposure; lipophilicity; permeability; pharmacokinetics; preclinical; solubility; variability