Preclinical pharmacokinetics and metabolism of
MK-0518, a potent HIV Integrase inhibitor in phase III
clinical trials
Odalys Gonzalez Paz, Marina Taliani, Annalise Di Marco, Edith Monteagudo, Fabio
Bonelli, Fabrizio Fiore, Massimiliano Fonsi, Francesca Naimo, Maria Verdirame, Anna
Alfieri, Isabella Marcucci, Vincenzo Summa, Michael Rowley, Ralph Laufer

IRBM-Merck Research Laboratories Rome, Pomezia (Rome), Italy Introduction
In vivo and in vitro metabolites of Radiochromatogram of rat urine and bile post All currently licensed oral agents for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infection target the two retroviral enzymes, Reverse Transcriptase and Protease. Although these agents have proven to be highly effective when used in combination, the spread of multi-drug resistant variants, insufficient therapeutic durability and increased awareness of the toxicities related to chronic administration of many of these therapies support a need for new treatment options. The retroviral enzyme integrase is required to catalyze the insertion of the HIV-1 cDNA into the genome of the host cell. Although integration is essential for HIV-1 replication, to date there are no approved antiviral agents that specifically Drug metabolism and disposition of MK-0518 a potent inhibitor of this enzyme was characterized in animals in support of its selection for further development.
Characterization of the human UGTs isoforms In vitro and in vivo pharmacokinetic and metabolic properties of MK-0518 were involved in the glucuronidation of MK-0518 studied in several preclinical species.
Glucuronidation of L-900612 (10 uM) in human UGT supersomes (0.5
mg/ml) in the presence of UDPGA
Pharmacokinetic parameters (Mean ± SD) of Pharmacokinetic parameters (Mean ± SD) of MK-0518 in rats, rabbits, dogs and monkeys Prediction of in vivo clearance in man fu / BP × Q × CLin Predicted human
Plasma clearance = 3.5 ml/min/kg
y = 0.7017x + 2.0062
R2 = 0.8789
Absorption Kinetics (Mean ± S.D.) of MK- CL is determined in vitro using hepatic microsomes supplemented with NADPH For some drugs, in particular those mainly metabolized by glucuronidation, this method leeds to underestimation of in vivo clearance. Prediction may be improved MK0518 (percentage of the dose recovered) by using an allometric correction factor for differences in body weight (W) (Lave et Observed human plasma AUC after a single oral dose at 3 mg/kg = 17 µM x If human oral bioavailability is similar to rat and dog (45-77%) Plasma clearance = 2.8 – 4.8 ml/min/kg
aUrine and bile collected for 24 hr postdose.
bUrine collected for 48 hr postdose.
Compound quantified by LC-MS/MS.
Potassium salt dosed in 1% methylcellulose Conclusions
The pharmacokinetic properties of MK-0518 in animals were characterized by moderate-low plasma clearance, good bioavailability and modest binding toplasma proteins. Elimination occurs mainly by metabolism. The major metabolite detected in rat urine and bile, dog urine, and in rat, dog, human and rhesus microsomal and hepatocyte incubations was the 5-O-glucuronide conjugate. Considering the in vitro intrinsic clearance, protein binding, blood-to-plasma partition and in vivo clearance in preclinical species a low clearance in humans was predicted. MK-0518 did not inhibit the major cytochrome P450 and UGT enzymes in human liver microsomes, and did not induce CYP3A4 in human hepatocytes, indicating no potential for causing drug-drug interactions. Results from these studies pointed out potentially favorable pharmacokinetic properties of MK-0518 in humans and this was confirmed in clinical studies.


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