February 27, 2002
M.B. Wire and colleagues from GSK, Buffalo Clinical Research Center, Albany Medical College, and Johns Hopkins conducted this PK study in normal volunteers. There is considerable interest in amprenavir-like compounds utilizing ritonavir boosting. There is also interest in using protease inhibitors in combination with NNRTIs. One problem with using protease inhibitors with NNRTIs is that the two most widely used NNRTIs (nevirapine and efavirenz) interact with the protease inhibitors often yielding lower plasma levels of protease inhibitors.
An earlier study (CID 2000; 30: 313-318) found that efavirenz significantly decreased amprenavir (APV) levels. Another previous study found that co-administration of 200 mg ritonavir (RTV) with amprenavir counteracted the effect of efavirenz.
In this study, 31 subjects started GW908 (pro-drug of amprenavir) 700 mg BID (twice a day) plus ritonavir 100 mg BID for 14 days (period 1). Half of the subjects then took GW908 700 mg BID plus efavirenz 600 mg a day plus either ritonavir 100 mg or 200 mg BID for an additional 14 days (period 2). Due to various withdrawals, 28 patients completed period 1 while 14 patients received the 100 mg ritonavir dose in Period 2 and 12 patients received the 200 mg ritonavir dose. PK sampling was performed on day 14 of each of the study periods.
Plasma amprenavir concentrations were maintained when ritonavir 100 mg BID was co-administered with GW908 (the GW908 formulation was a single 700 mg capsule) while the study subjects also were taking standard doses of efavirenz. The use of a higher dose of ritonavir (200 mg BID) did not significantly increase the plasma APV levels. The most common diverse events were loose stools (26 percent), diarrhea (23 percent), fatigue (26 percent), headache (23 percent), dizziness/lightheadedness (19 percent), and rash (16 percent). Cholesterol increased by 28.5 mg/dL after 14 days of GW908 and 100 mg ritonavir BID (end of period 1) while triglycerides increased 73.6 mg/dL. At the end of period 2, cholesterol increased an average of 48.7 mg/dL for the 100 mg ritonavir group and 43.3 mg/dL for the 200 mg ritonavir group. For the change in triglyceride levels at the end of period 2, the ritonavir 100 mg group increased 111 mg/dL while the ritonavir 200 mg group increased 201 mg/dL.
This study in normal volunteers suggests that ritonavir 100 mg BID is sufficient to maintain amprenavir levels when GW908 is co-administered with efavirenz. The RTV 100 mg BID dose was associated with lower triglyceride levels than RTV 200 mg BID. This information would be useful as a starting point for studies using GW908 with efavirenz in HIV-infected subjects, but needs to be confirmed in that population.
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