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 testosterone tolbutamide dextromethorphan Compound O-demethylation hydroxylation hydroxylation Compound
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 × CLinPredicted 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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