Variability in Activity of Hepatic CYP3A4 in Patients Infected with HIV

Slain, Douglas; Pakyz, Amy; Israel, Debra S.; Monroe, Sara; Polk, Ron E.

doi:10.1592/phco.20.11.898.35262

Cited by 37 publications

(33 citation statements)

References 42 publications

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“…In addition, CYP3A4 activity appears to be more variable in HIV-positive patients than in non-infected subjects. [243] Moreover, Lee et al demonstrated that AIDS patients with acute illnesses had altered patterns of drug metabolism. [244] Data collected from studies performed in healthy volunteers should thus be extrapolated carefully to HIVinfected individuals.…”

Section: Discussionmentioning

confidence: 99%

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

Maat

Ekhart

Huitema

et al. 2003

Clinical Pharmacokinetics

140

141

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Section: Discussionmentioning

confidence: 99%

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

Maat

Ekhart

Huitema

et al. 2003

Clinical Pharmacokinetics

140

141

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“…In addition, CYP3A4, the enzyme responsible for the metabolism of all PIs and NNRTIs, shows marked interindividual variability (32,33). Moreover, its activity appears to be even more variable in HIV-positive patients than in noninfected subjects (34). Also, habits like intake of alcohol and cigarette smoking could possibly interfere with the metabolism of drugs.…”

Section: Discussionmentioning

confidence: 99%

Subtherapeutic Antiretroviral Plasma Concentrations in Routine Clinical Outpatient HIV Care

Maat¹,

Huitema²,

Mulder³

et al. 2003

Therapeutic Drug Monitoring

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Summary:The objective of this study was to evaluate plasma concentrations of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) within several dosing schemes in a cohort of HIV-infected patients in routine clinical practice and to find possible explanations for subtherapeutic plasma concentrations. Patients were included if a PI or NNRTI was part of their antiretroviral regimen, at least one plasma concentration was obtained, and a complete medication overview from community pharmacy records was available. The study period was from January 1998 to September 2001. Each plasma concentration was related to median plasma concentrations of a pharmacokinetic reference curve, yielding a concentration ratio (CR). A cutoff CR was defined for each antiretroviral drug per specific regimen, discriminating between Նtherapeutic and subtherapeutic concentrations. For the patients with subtherapeutic concentrations, it was sorted out whether drug interactions, adverse events and self-reported symptoms, or nonadherence could be the cause of the lower than expected plasma concentration. Ninety-seven HIV-infected patients fulfilled the criteria. During the defined period, 1145 plasma concentrations were available (median, 11; interquartile range, 8-14). Three hundred fourteen (27.4%) plasma concentrations were classified subtherapeutic. Drug interactions (2; 0.6%), adverse events and self-reported symptoms (67; 21.3%), and nonadherence (14; 4.5%) could only partly explain the subtherapeutic drug levels. Consequently, a large number of the subtherapeutic plasma concentrations (73.6%) remained inexplicable. A high number of subtherapeutic plasma concentrations were observed. No clear causes were found; thus, corrective measures will be difficult to employ. Therefore, therapeutic drug monitoring (TDM) must maintain its crucial place in routine clinical care to be able to identify patients who need extra attention so that therapeutic plasma concentrations are achieved.

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“…Comparison between the study by Saah et al and Gerber et al suggested that the total exposure, C min , and C max of IDV and RTV are lower in HIV-infected patients than in seronegative subjects (11,25). Slain et al observed greater variability in hepatic activity of CYP3A4 in HIV-positive patients compared to HIV-negative healthy controls, which may have contributed to these findings (26). In addition, Acosta et al found that protease inhibitor-naïve patients with undetectable HIV RNA who were started on a protease inhibitor regimen had statistically higher C 8h and AUC 0-8 values than similarly treated patients with detectable HIV RNA at baseline (3).…”

Section: Discussionmentioning

confidence: 95%

Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients

Rhame

Rawlins

Petruschke

et al. 2004

Antimicrob Agents Chemother

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max ]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C min ratio of the combination compared to IDV alone regimen would be >2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C min , AUC 0-24 , and C max for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM ⅐ h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C min (90% CI, 4.0, 9.3), an increase in AUC 0-24 (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C max . Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C min for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C max was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.Single-protease inhibitor regimens significantly reduced the morbidity and mortality associated with human immunodeficiency virus (HIV) following their introduction (19,20). More recently, boosted protease inhibitor regimens combined ritonavir (RTV) with a second protease inhibitor to achieve higher sustained levels of the second protease inhibitor than seen when it was given as part of a single-protease inhibitor regimen. The boosted protease inhibitor regimens may be more effective in suppressing HIV strains with resistance to antiretroviral therapy, including resistance to the second protease inhibitor (2,9,10,18,22,32). In addition, boosted protease inhibitor regimens may be administered less frequently and without regard to meals, potentially improving patient adherence (2, 9, 10, 18, 22, 32). RTV's inhibition of the cytochrome P-450 CYP3A4 enzyme, the primary enzyme in the metabolism of most protease inhibitors, changes the pharmacokinetics of the second protease inhibitor, with elevations of minimum drug concentration (C min ) and area under the concentrationtime curve (AUC) contributing to improved clinical efficacy (2, 10). In addition, RTV's inhibition of P-glycoprotein transport proteins may also contribute to increased concentration of a concomitantly administered protease inhibitor in plasma (33).Indinavir (IDV) is approved for administration every 8 h (q8h) at 800 mg without food (28). Combinations of IDV at 400 to 800 mg and RTV at 100 to 400 mg twice a day (b.i.d.) demonstrated at least equivalent to (and in many cases much higher than) the C min and AUC at 24 h (AUC 24 ) of IDV at 800 mg q8h in normal volunteers and can be administered with food (25). The trough levels maintained with the b.i.d. combinations were above the concentration necessary to inhibit 95% of viral growth of wild-type HIV-1 seen in the absence of drug (8). The most-studied boosted IDV regimen is IDV at 800 mg plus RTV at 100 mg q12h (4,7,21,31). A combination regimen of IDV...

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Variability in Activity of Hepatic CYP3A4 in Patients Infected with HIV

Cited by 37 publications

References 42 publications

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

Drug Interactions Between Antiretroviral Drugs and Comedicated Agents

Subtherapeutic Antiretroviral Plasma Concentrations in Routine Clinical Outpatient HIV Care

Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients

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