The second wave of HAART: Combining MK 518 plus TMC 125 or Maraviroc

Now, patients with HIV multidrug resistance can start three active drugs in three different expanded access programs! This is the first time this has been possible in the 25 years of the AIDS epidemic. The closest thing to this wonderful time was the 1996-1998 period.

This information was provided by Merck (Feb 20, 2007):

Co-Administration of MK-0518 and TMC125

Merck & Co, Inc and Tibotec Pharmaceuticals Ltd. have jointly reviewed the available pharmacokinetic data on TMC125 and MK-0518 and concluded that co-administration of TMC125 and MK-0518 may be allowed for patients in the MK-0518 expanded access program. This assessment is based upon data collected from a drug-drug interaction pharmacokinetic study in 19 healthy volunteers to evaluate the potential interaction of the two compounds.
Preliminary safety data from the study indicated that co-administration of MK-0518 and TMC125 was generally well tolerated. Preliminary MK-0518 pharmacokinetic data showed a modest effect of TMC125 on MK-0518 pharmacokinetics (mean decrease in AUC of ~10%, in Cmax of ~11%, and C12 hr of ~34%). This overall modest decrease in MK-0518 pharmacokinetic parameter values is not felt to require dose adjustment based on the efficacy demonstrated by MK-0518 doses ranging from 100 to 600 mg in treatment-naïve patients and from 200 mg to 600 mg in treatment-experienced patients. Preliminary TMC125 pharmacokinetic data showed essentially no meaningful effect of MK-0518 on TMC125 pharmacokinetics (~4 to 17% mean increase in TMC125 pharmacokinetic parameter values).

Co-administration of MK-0518 and Maraviroc

Merck & Co, Inc. has reviewed the available pharmacokinetic data on MK-0518 and Maraviroc and concluded that co-administration of MK-0518 and Maraviroc may be allowed for patients in the MK-0518 expanded access program.

Maraviroc is predominantly metabolized by CYP3A4 with renal clearance contributing less than 25% of total clearance. Maraviroc has been shown to have no effect on the major cytochrome P450s in vitro, at clinically relevant concentrations. Maraviroc has also been shown to have no clinically relevant effect on CYP3A4 activity. As such, Maraviroc is not expected to affect the pharmacokinetics of other co-administered drugs metabolized by CYP450. Maraviroc exposure is affected by modulators of CYP3A4 activity.

MK-0518 is primarily cleared by metabolism via glucuronidation (by UGT1A1) with a small renal component. In vitro studies have confirmed it is not a substrate or inhibitor/inducer of cytochrome P450s. A clinical study with MK-0518 showed no effect on midazolam pharmacokinetics.

Based on these data, Maraviroc and MK-0518 are not expected to interact with each other and may be co-administered in expanded access programs without dose adjustment of either agent.
MK-0518 Protocol 023 Expanded Access Program Amendment

A protocol amendment is in preparation to allow enrollment of patients who have:
-chronic renal insufficiency including patients undergoing dialysis
-failed an NNRTI containing regimen but do not have documented genotypic or phenotypic resistance to NNRTIs.
All other inclusion/exclusion criteria remain unchanged and patients need to have documented phenotypic or genotypic resistance to both NRTIs and PIs.

Prior to approval of the protocol amendment, enrollment of these patients will be permitted as a protocol deviation and it will be necessary to obtain a sponsor consultation Form from Parexel and IRB/ERC approval for each individual patient.

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