New Data on MK-0518 Drug Interactions

A number of studies presented at the recent ICAAC looked at interactions between the novel integrase inhibitor MK-0518 and various approved antiretroviral drugs.

MK-0518 is primarily metabolized by glucuronidation, and does not appear to inhibit or induce cytochrome P450 (CYP450) enzymes, which metabolize many drugs in the liver.

Study 1

In the first study, researchers evaluated the effects of ritonavir and efavirenz on MK-0518. Unlike MK-0518, the protease inhibitor ritonavir (Norvir) has a strong effect on the CYP450 system and interacts with many other drugs. Efavirenz (Sustiva/Stocrin), a non-nucleoside reverse transcriptase inhibitor, also has both inhibitory and inductive potential.

In one placebo-controlled assessment, 12 subjects received 400 mg MK-0518 during Period 1, and 100 mg ritonavir every 12 hours for 16 days with 400 mg MK-0518 added on Day 14 during Period 2.

In another assessment, 12 healthy subjects received 400 mg MK-0518 during Period 1, and 600 mg efavirenz at bedtime for 14 days with 400 mg MK-0518 added on Day 12 during Period 2.

The researchers assessed pharmacokinetic parameters including area under the curve (AUC), 12-hour concentrations (C12 hr), and maximum concentrations (Cmax).

Results

No serious adverse events (AEs) and no discontinuations due to MK-0518 related AEs were reported.

In the presence of ritonavir, MK-0518 PK parameters were not affected:
- C12 hr GMR = 0.99;
- AUC0 = 0.84;
- Cmax = 0.76.

In the presence of efavirenz, MK-0518 AUC0-?, Cmax, and C12 hr were modestly reduced:
- C12 hr GMR = 0.79;
- AUC0 = 0.64;
- Cmax = 0.64.

There were no substantial differences in Tmax or t½ (half-life).

"MK-0518 co-dosed with ritonavir or efavirenz is generally well tolerated," the researchers concluded. "Plasma levels of MK-0518 are not affected when co-dosed with ritonavir. Plasma levels of MK-0518 are modestly reduced when co-dosed with efavirenz without otherwise altering the [pharmacokinetic] profile, suggesting lack of a clinically meaningful effect."

Study 2

In the second study, researchers assess the effect of ritonavir-boosted tipranavir (Aptivus) on MK-0518. This protease inhibitor combination has both inhibitory and inductive potential, including potential induction of glucuronosyltransferases.

In an open-label study, 15 healthy subjects received 400 mg MK-0518 every 12 hours for 4 days during Period 1; 500/200 mg tipranavir/ritonavir every 12 hours for 7 days during Period 2; and 400 mg MK-0518 plus 500/200 mg tipranavir/ritonavir every 12 hours for 4 days during Period 3; there was no washout between Periods 2 and 3.

Results

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

In the presence of tipranavir/ritonavir, C12 hr of MK-0518 was modestly decreased (GMR = 0.45).

MK-0518 AUC0-12 hr (0.76) and Cmax (0.82) did not change substantially.

The researchers concluded that, "MK-0518 co-dosed with tipranavir/ritonavir is generally well tolerated. MK-0518 C12 hr is modestly decreased by tipranavir/ritonavir, and MK-0518 AUC0-12 hr and Cmax are not substantially affected."

Study 3

The third study looked at interactions between MK-0518 and the nucleotide reverse transcriptase inhibitor tenofovir DF (Viread). Tenofovir is primarily eliminated by a combination of glomerular filtration and active tubular secretion. There are no data to suggest that an interaction between tenofovir and MK-0518 would be anticipated, but there have been unexpected interactions between tenofovir and other antiretroviral agents.

In an open-label study, 10 healthy subjects received 400 mg MK-0518 every 12 hours for 4 days during Period 1; 300 mg once-daily tenofovir for 7 days during Period 2; and 400 mg MK-0518 every 12 hours plus 300 mg once-daily tenofovir for 4 days during Period 3; there was no washout between Periods 2 and 3.

Results

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

One subject discontinued due to laboratory AEs of increased ALT and AST following administration of tenofovir alone for 7 days.

In the presence of tenofovir DF, C12 hr of MK-0518 was unchanged (GMR = 1.03).

MK-0518 AUC0-12hr (1.49) and Cmax (1.64) were modestly increased.

In the presence of MK-0518, tenofovir Cmax decreased slightly (0.77), with less effect on AUC0-24 hr (0.90) and C24 hr (0.87).

The researchers concluded that, "MK-0518 co-dosed with tenofovir DF is generally well tolerated. MK-0518 C12 hr is not substantially affected by tenofovir DF, and MK-0518 AUC0-12hr and Cmax are modestly increased. MK-0518 had no clinically important effect on serum levels of tenofovir.

Merck & Co., Inc., Whitehouse Station, NJ; Thomas Jefferson Univ., Philadelphia, PA; SGS Life Sci. Services, Antwerp, Belgium.

Merck & Co., Inc., Whitehouse Station, NJ; Prism Res., St. Paul, MN.

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

10/10/06

References

M Iwamoto, L A Wenning, A S Petry, and others. Minimal Effect of Ritonavir (RTV) and Efavirenz (EFV) on the Pharmacokinetics (PK) of Mk-0518. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract A-373.

L A Wenning, H Hanley, J Stone, and others. Effect of Tipranavir + Ritonavir (TPV + RTV) on Pharmacokinetics of MK-0518. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract A-374.

L A Wenning, E Friedman, J T Kost, and others. Lack of a Significant Drug Interaction Between MK-0518 and Tenofovir Disoproxil Fumarate (TDF). 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract A-375.

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