Pharmacokinetics and Dosing of MK-0518 in Healthy Volunteers

MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV (IC95 = 33 nM in 50% human serum). At the recent ICAAC, researchers presented data showing that 57%-67% of treatment-experienced patients with drug-resistant HIV achieved viral loads below 50 copies/mL 24 days after starting MK-0518.

Researchers also presented data on the pharmacokinetics (PK) and safety of MK-0518.

Study 1

In one analysis, PK and safety data were collected after healthy HIV negative volunteers received a single or multiple doses of MK-0518.

In a dose-escalation study, 24 healthy males received 10 to 1600 mg single doses of MK-0518 (lactose formulation) or placebo in the fed or fasted state. In addition, 15 healthy men received single 400 mg doses of MK-0518 (lactose formulation and poloxamer formulation) and 8 women received single-dose 400 mg MK-0518 (lactose formulation only), or else placebo. In the multiple-dose analysis, 40 healthy males received 100 to 800 mg MK-0518 (lactose formulation) or placebo every 12 hours for 10 days.

Results

There were no serious adverse events (AEs) reported and no discontinuations due to AEs.

In the single-dose analysis, MK-0518 lactose formulation was rapidly absorbed, with median Tmax at 0.5-1.3 hrs.

Concentrations declined in a biphasic manner with initial phase t½ at about 1 hr and terminal phase t½ at about 7-12 hours.

Moderate and high-fat meals had no clinically meaningful effect on PK parameters.

Area under the curve (AUC0-?) was similar in males and females.

The MK-0518 poloxamer formulation had a C12 hr (12-hour concentration) similar to that of the lactose formulation, but with lower AUC0-? and Cmax.

In the multiple-dose analysis, a steady state was achieved within 2 days.

There was little accumulation of AUC0-12 hr (0.9 to 1.2) and Cmax (0.7 to 1.2), and modest accumulation of C12 hr (1.2 to 1.6).

The researchers concluded that, "MK-0518 is generally well tolerated and exhibits a PK profile supportive of twice daily dosing."

Study 2

A second analysis investigated routes of excretion of MK-0518 metabolites to determine plasma concentrations and establish metabolism pathways in humans.

In this study, 8 healthy male subjects received a single oral 200 mg dose of MK-0518 with a radioactive tag to enable tracing ([14C]MK-0518; 200 µCi). Plasma, urine, and fecal samples were collected for up to 240 hours after dosing. Metabolites were identified in excretions and plasma using LC-MS/MS. In vitro studies were performed using cDNA-expressed UDP-glucuronosyltransferases (UGTs) and native human liver microsomes.

Results

Radioactivity was eliminated in substantial amounts in both the urine (32%) and feces (51%).

The elimination of radioactivity was rapid, as the majority of the recovered dose was attributable to samples collected within 24 hours.

In urine, two components were detected (MK-0518 and its glucuronide derivative, M2), while in feces only MK-0518 was present.

The MK-0518 parent compound and M2 accounted for 8% and 23% of the dose recovered in urine, respectively.

The major circulating entity, MK-0518, represented 69% of the total radioactivity; remaining radioactivity in plasma was accounted for by M2.

In human liver microsomes, there was no oxidative metabolism of MK-0518.

MK-0518 was not an inhibitor of cytochrome P450 enzymes, and did not induce CYP3A.

Studies using form-selective chemical inhibitors and cDNA-expressed UGTs indicated UGT1A1 was the main isoform responsible for formation of M2.

The researchers concluded that, "The major mechanism of clearance of MK-0518 in humans is UGT1A1-mediated glucuronidation."

The fact that MK-0518 did not inhibit cytochrome P450 (CYP450) enzymes or induce CYP3A is significant because this suggests the new agent will have limited interactions with ritonavir (Norvir) and other antiretroviral agents metabolized via the CYP450 system.

Merck & Co., Inc., West Point, PA; Merck & Co., Inc., Whitehouse Station, NJ; SFBC Intl., Miami, FL.

Merck & Co., Inc., Whitehouse Station, NJ; SGS Life Sci. Services, Antwerp, Belgium; SFBC Intl., Miami, FL.

10/10/06

References

A S Petry, L A Wenning, M Laethem, and others. Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-0518 in Healthy Subjects. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract A-376.

K Kassahun, I MCIntosh, D Hreniuk, and others. Absorption, Metabolism and Excretion of MK-0518, a Potent HIV-1 Integrase Inhibitor, in Healthy Male Volunteers. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract A-372.

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