Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time C
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Research Article Prediction of Human Pharmacokinetics of Fomepizole from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles Ravi Kumar Jairam,1 Sadanand Rangnathrao Mallurwar,1 Suresh P. Sulochana,1 Devaraj V. Chandrasekhar,1 Umesh Todmal,1 Ravi Kanth Bhamidipati,1 Wolfgang Richter,2 Nuggehally R. Srinivas,3 and Ramesh Mullangi1,4
Received 13 February 2019; accepted 23 May 2019; published online 18 June 2019 Abstract.
Fomepizole is used as an antidote to treat methanol poisoning due to its selectivity towards alcohol dehydrogenase. In the present study, the goal is to develop a method to predict the fomepizole human plasma concentration versus time profile based on the preclinical pharmacokinetics using the assumption of superimposability on simulated time course profiles of animals and humans. Standard allometric equations with/without correction factors were also assimilated in the prediction. The volume of distribution at steady state (Vss) predicted by simple allometry (57.55 L) was very close to the reported value (42.17 L). However, clearance (CL) prediction by simple allometry was at least 3-fold higher to the reported value (33.86 mL/min); hence, multiple correction factors were used to predict the clearance. Both brain weight and maximum life span potential could predict the CL with 1.22- and 1.01-fold difference. Specifically, the predicted Vss and CL values via interspecies scaling were used in the prediction of series of human intravenous pharmacokinetic parameters, while the simulation of human oral profile was done by the use of absorption rate constant (Ka) from dog following the applicability of human bioavailability value scaled from dog data. In summary, the findings indicate that the utility of diverse allometry approaches to derive the human pharmacokinetics of fomepizole after intravenous/oral dosing.
KEY WORDS: fomepizole; clinical pharmacokinetics; interspecies scaling; preclinical pharmacokinetics; simulations.
INTRODUCTION Fomepizole, also known as 4-methylpyrazole (4-MP), competitively inhibits alcohol dehydrogenase (ADH) both in vitro (1– 3) and in vivo (4,5). Just recently, the Czech Republic witnessed increased outbreaks of acute methanol poisoning leading to health hazard and mortality (6), which generally occur by misuse/ accident or suicide attempts. Such episodes of methanol poisoning cases are treated by administration of antidotes like ethanol or fomepizole. Both these drugs reverse the methanol poisoning by antagonizing ADH, which can effectively block the conversion of methanol to formaldehyde. Due to several unfavorable attributes of ethanol (irregular pharmacokinetics, possibility of overdosing etc.), currently, it is not being used as an antidote for methanol poisoning (7). Fomepizole is another effective antidote with 1
Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore, 560 022, India. 2 TUBE Pharmaceuticals GmbH, Leberstr. 20, A-1110, Vienna, Austria. 3 Jubilant Generics Limited, Noida, Uttar Prades
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