IAS 2003 (International AIDS Society 2003) Abstracts

Nevirapine induces the metabolism of indinavir. Peytavin et al performed this 72-week study to evaluate the effect of increasing the dose of indinavir to 1000mg TID (normal dosage 800mg TID per Crixivan package insert Jan '03) when co-administered with nevirapine 200mg BID. Nevirapine PK was compared to lamivudine in the presence of indinavir and stavudine.

Comparing the lamivudine group to the nevirapine group, the median C_min of indinavir at week 8 trended to, but did not reach significance. The median C_max of indinavir at both weeks 8 and 24 was not different between the lamivudine and nevirapine groups. Regardless of the regimen, the week 32 (p = 0.001) and week 72 (p = 0.04) HIV-1 RNA viral load (<20copies/ml) was associated with an adequate C_min. The number of side effects at week 24 was associated with the C_min of indinavir (p = 0.03); however, no association was found with the indinavir C_max. There was also a significant association between the number of nevirapine side effects after week 8 and the Cmin of nevirapine at week 8 (p < 0.001). The authors concluded that therapeutic drug monitoring (TDM) might be useful to help predict the potential for adverse effects as well as how the virus is responding to the treatment.

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Pharmacokinetics of Rifabutin Co-administered with Lopinavir/Ritonavir (LPV/r) in HIV Patients Affected by Tuberculosis (TB)
S Bonora, M Boffito, A D'Avolio, M Sciandra, D Aguilar, F Canta, A Maiello, A Lucchini, I Arnaudo, I Dal Conte, I Meoli, D Back, G Di Perri

Decreased rifabutin (RIF) doses are recommended when co-administered with protease inhibitor regimens. Bonora et al studied the PK of RIF and lopinavir/ritonavir (LPV/r) in 4 HIV+ tuberculosis patients. Three of the patients (pts A, B, C) received RIF 300mg QD, LPV/r 400/100 BID, and 2 NRTIs, while the fourth patient (pt D) received RIF 150mg QD added to LPV/r 400/100 BID. The PKs of rifabutin are listed in the tables below.

The authors concluded that their evidence supports the use of lower dose RIF (150mg) in the presence of LPV/r. Therapeutic drug monitoring of RIF might be worthwhile due to high inter-subject variability in HIV patients.

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Nevirapine (NVP) Significantly Reduces Methadone Levels in HIV-Infected Patients
H Stocker, G Kruse, P Kreckel, C Herzmann, K Arasteh, H Eskoetter, J Claus, H Jessen, C Cordes, B Hintsche, F Schlote, L Schneider, and M Kurowski

Methadone is partially metabolized by CYP3A4 which is of concern for potential drug interactions. NVP is a known inducer of CYP3A4 which may lead to more frequent withdrawal symptoms. Stocker et al studied 24 HIV-infected men on methadone in which NVP was added as part of a new or previous HIV regimen. Dose changes were initiated if subjects displayed symptoms of withdrawal. PK measurements were calculated using 12 hour sampling before and 28 days after NVP initiation. The authors found that NVP significantly (P<0.01) decreased the dose-adjusted AUC of methadone by 40%. Methadone AUC changes were highly variable among subjects and ranged from mild increases to decreases of as much as 67%. To balance the increased methadone metabolism by NVP, the authors estimate that a 66% (range of 0% to 203%) increase in mean methadone dose would be required. The mean methadone dose increase in this study was 24% (range of 0% to 80%). The mean NVP trough at day 28 was 3760 ng/ml (range of 1620-7580 ng/ml). The authors concluded that doses of methadone adjusted to each individual's needs may be required when co-administered with NVP.

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Abstract 869

Tenofovir DF (TDF) Does Not Affect The Pharmacokinetics or Pharmacodynamics of Methadone (MTH)
P Smith, B Kearney, D Cloen, B Booker, S Liaw, K Yale, C Haas, C Berenson, D Coakley, J Flaherty

Smith et al performed an open-label, fixed sequence study with 14 HIV-negative subjects on stable doses of MTH (range = 40-110mg/day) to determine the effects of TDF on the PK/PD of MTH. This study was completed using directly observed treatment (DOT). Methadone PK was determined after 14 days of DOT of MTH and then repeated adding TDF 300 mg QD for 14 days. Of the 13 patients who completed the study, MTH AUC and Cmax levels were equivalent regardless of TDF use (geometric mean ratio (90% CI) = 1.05 (0.98, 1.13) and 1.05 (0.97, 1.14), respectively). Both the R and S enantiomers of methadone were equivalent. The authors concluded that TDF does not affect MTH levels.

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The Effect of Efavirenz (EFV) and Nelfinavir (NFV) on the Pharmacokinetics (PK) of Pravastatin (P)
JG Gerber, S Rosenkranz, CJ Fichtenbaum, B Alston, SW Brobst, Y Segal, J Segal, and A Aberg

Pravastatin (P) is the preferred HMGCoA reductase inhibitor for HAART-induced hyperlipidemia since it has the least drug-drug interactions with PIs and NNRTIs. Gerber et al performed a within-subject study to determine the potential PK effects of P with efavirenz (EFV) or nelfinavir (NFV). P 24-hour PK profiles were determined in seronegative subjects after 3 days of therapy alone and repeated after 12 days of NFV and 14 days of EFV. The authors found that NFV administration resulted in a median P AUC_24h decrease of 47% (range: -65% to 10%, n = 14). When P was administered with EFV, the median P AUC_24h was decreased by 40% (range: -73% to +28%, n = 11).

The authors concluded that despite P being the HMGCoA-reductase of choice; due to induction of metabolism, higher doses of P may be necessary to achieve desired cholesterol levels when given with NFV or EFV.

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Compiled by Jeff Dearman.
HIV conference search for drug-drug, drug-food, or drug-herbal interactions