Summary of other PK studies

1 November 2003. Related: PK and drug interactions.

David Margolis, NATAP.org

There were a large number of other PK and interaction studies included at the conference. Summary results are included below but please review the abstract for full details.

• No PK interaction was observed when FTC was administered with tenofovir or zidovudine.
• n a 35-day PK study of tenofovir and Kaletra, PK of lopinavir alone and RTV alone were unaffected by tenofovir. Tenofovir levels increased 32%, there were no serious adverse events reported. (In Study GS-908 TDF Compassionate Access Study (n=296), the incidence of confirmed changes in serum creatinine to >2.0 mg/dl or serum phospohorous <1.5 mg/dl was <1%. Five patients (1.8%; 5/271) experienced serum creatinine changes leading to TDF discontinuation: one patient developed Fanconi’s Syndrome (also experienced during prior use of high dose adefovir).
• n a 35-day PK study of tenofovir and Kaletra, PK of lopinavir alone and RTV alone were unaffected by tenofovir. Tenofovir levels increased 32%, there were no serious adverse events reported. (In Study GS-908 TDF Compassionate Access Study (n=296), the incidence of confirmed changes in serum creatinine to >2.0 mg/dl or serum phospohorous <1.5 mg/dl was <1%. Five patients (1.8%; 5/271) experienced serum creatinine changes leading to TDF discontinuation: one patient developed Fanconi’s Syndrome (also experienced during prior use of high dose adefovir).
• Atorvastatin has no clinically significant effect on 908. Coadministration of 908, alone or with ritonavir, significantly increases atorvastatin exposure. Atorvastatin doses < 20mg/day should be used with 908 or another statin that is less dependent on CYP3A4 metabolism should be considered.
• Both tenofovir and UK-427857, an investigational antagonist of the CCR5 receptor, do not affect the activity of oral contraceptives
• Coadministration of the lower dose of 250 mg ddI-EC with 400 mg atazanavir and 300 mg tenofovir with food results in adequate ddI exposure. However, atazanavir levels are significantly reduced when given with tenofovir (with or without ddI). The addition of ritonavir may be required to overcome this, thus presenting challenges to the construction of a simple QD regimen that includes atazanavir.
• Saquinavir/ritonavir 2000/100mg once a day achieves levels close to 1600/100 twice a day, and might be studied for use in patients without PI resistance. However, trough levels at the end of dosing are unacceptably low when 2000/100 is given, particularly so if PI resistance is present.
• The intracellular half-life of the active metabolite of abacavir, carbovir, was reported to be 20.6 hours. This would be sufficient for once a day dosing of abacavir, and suggests that a mechanism other than insufficient intracellular drug concentrations must account for virological failure in recent studies using once a day abacavir/tenfovir/3TC.
• Lopinavir levels were reported from assays of 31 CSF-plasma pairs from 26 HIV-infected individuals taking lopinavir-containing antiretroviral regimens. LPV was detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication.