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PK Report-Double Boosted Protease Inhibitor Regimens: Reyataz/SQV/r; SQV/Fosamprenavir/r; PK highlights
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Written for NATAP by Ronald Reisler, MD, MPH, Institutes of Human Virology, University of Maryland
11th Annual Retrovirus Conference, Feb 8-11, 2004, San Francisco
Reyataz plus Saquinavir Boosted by Lo-Dose Ritonavir
Boffito reported in abstract 607 on the PK (pharmacokinetics; aka drug levels in blood) of the combination of atazanavir plus saquinavir boosted by low-dose ritonavir (ATV/SQV/RTV) 300/1600/100 in 20 HIV+ patients (2 females; mean age 41 years; median CD4 442 cells/mm3).
They administered SQV/RTV 1600/100 mg once daily with a 20-g fat meal. On day 2, ATV 300 mg once daily was added to the regimen for 30 days. Safety analysis was performed at screening, D1, 11, 31, and follow-up. No significant changes in ALT, AST, glucose, total cholesterol and triglycerides were observed, whereas total and indirect bilirubin increased by 5 times after 10 days of ATV therapy (median, range: 36, 11-139, and 32, 9-128 mmol/L, respectively). Four patients developed scleral icterus and 2 jaundice. ATV concentrations were in accordance with the ATV concentrations observed in pts with ATV/RTV. The authors concluded that the addition of ATV to SQV/RTV increased SQV AUC, Cmax and Ctrough by 60%, 42% and 112% respectively (p <0.05). RTV and ATV may have independent mechanisms of boosting SQV and other CYP3A4 substrates. (Reviewer's note: an optimal dose for this regimen remains to be worked out. Perhaps ATV/SQV/RTV 300/1000/100 once daily may an option worth pursuing).
Saquinavir plus Fosamprenavir Boosted by Ritonavir
Boffito reported in abstract 608 on the PK of the combination of SQV/433908/RTV(908 is fosamprenavir: new formulation of amprenavir). They studied the pharmacokinetics of 18 HIV+ patients (1 female; mean age 42 years) on SQV/r 1000/100 mg twice daily.
Patients were given SQV/r 1000/100 mg with a 20-g fat meal on day 1; on day 2 they were switched to SQV/fAPV/r 1000/700/100 mg twice daily, and on day 12 to 1000/700/200 mg twice daily. Safety analysis was performed at screening, on day 1, 11, and 22 and at follow-up. At screening, mean ±SD CD4 cell count was 442±233/mm3 and plasma HIV-RNA <200 copies/mL in all patients.
No significant changes in ALT, AST, glucose, or total cholesterol triglycerides were observed. SQV pharmacokinetic data on 17 patients are summarized. On day 11, SQV AUC0-12 (GMR, 95%CI: 0.86, 0.73 to 1.19), Ctrough (0.76, 0.62 to 1.19), and Cmax (0.91, 0.79 to 1.23) showed a not statistically significant decrease. On day 22, SQV AUC0-12 (GMR, 95%CI: 1.12, 0.88 to 1.73), Ctrough (1.03, 0.80 to 1.79), and Cmax (1.20, 0.97 to 1.74) showed a not statistically significant increase. fAPV concentrations were not affected by SQV co-administration: all patients had an APV Ctrough >HIVWT-MEC (Geometric mean 1252 ng/mL day 11 and 1120 ng/mL day 22).
Boffito et. al conclude: SQV/fAPV/r was well tolerated. SQV AUC0-12, Ctrough and Cmax decreased by 14%, 24%, and 9% on D11 and increased by 12%, 3%, and 20% on D22. Based upon this small pk study the authors recommend when combining SQV/fAPV/r to use a dose of 1000/700/200 BID, although if SQV plasma level monitoring is available to insure adequate concentrations, then a reduced RTV dose of 100 mg BID could be administered. (Reviewer's note: currently this PI combination would be 8 pills twice daily).
ADDITIONAL IMPORTANT PK FACTS:
Abstract 136LB (Gries et al.): Ribavirin (800 mg/day) does not alter the intracellular phosphorylation or plasma pharmacokinetics of ZDV, 3TC, or d4T in HCV/HIV-co-infected patients when assessed after 8 to 12 weeks of combination therapy.
Abstract 600 (Kearney et al): Tenofovir pharmacokinetics are not significantly altered with hepatic impairment. TDF does not alter the pharmacokinetics of adefovir or RBV, 2 medications used to treat viral hepatitis.
Abstract 602 (Kaul et al.) D4T XR did not influence the pharmacokinetics of tenofovir and no dose modification is required when TDF is coadministered with D4T XR.
Abstract 603(Gerber et al.): Data from ACTG 5108 suggest that EFV, when used with simvastatin (SIM) or atorvastatin (ATR) therapeutically, can result in significant induction of their metabolism. The reduced inhibition of HMG-CoA reductase activity during co-administration of EFV may result in diminished antilipid efficacy at the usual doses of SIM and ATR. Some patients taking EFV may require titration to higher SIM and ATR doses to achieve target lipid goals, but this should only be attempted with increased monitoring for toxicity. SIM and ATR do not effect EFV PK.
Abstracts 609(Wynn Vezina et al), 611 (Corbett et al), 612 (Wire et al): Be very careful when using GW433908 (fosAPV) (or amprenavir) and LPV/r. fAPV and lopinavir (LPV)/ritonavir (RTV) are both inhibitors and inducers of CYP3A4. All 3 PIs are substrates for P-glycoprotein (P-gp) and have P-gp induction or inhibition properties. Wynn Vezina et al report that one can successfully use APV with LPV/r coupled with therapeutic drug monitoring (TDM). Of 12 subjects, 6 (50%) had LPV/r dose increases (533/133 mg, n = 2; 666/166 mg, n = 4) and 3/12 (25%) had APV dose increases (750 mg, n = 2; 900 mg, n = 1). One subject decreased LPV/r to 267/67 mg secondary to diarrhea. At 12 weeks, HIV RNA (copies/mL) decreased to 2.5log10 (1.3 to 5.0) and CD4 count (cells/mm3) increased to 225 (10 to 710). In 6 subjects with LPV dose increases, median C12h (ng/mL) went from 960 (833 to 2943) to 4465 (1752 to 7841). No adverse events resulted from PI dose increases. Pharmacokinetic parameters for LPV/r/APV were highly variable, indicating the magnitude of the interaction was poorly predictable. Optimal management of the complex interaction between LPV/r and APV may require pharmacokinetically-guided dose individualization. LPV/r and fAPV are generally poorly tolerated when used in combination. When fAPV is combined with LPV/r, plasma concentrations of APV are significantly reduced. Separating fAPV dosing 4 or 12 hours from lopinavir/r did not improve APV exposure (as compared to 0HR), but corrected LPV exposure (although increased RTV doses may have contributed). Further investigation is needed to determine an optimal dosing strategy when combining fAPV and LPV/RTV.
Abstract 614 (Morse et al) : If you want to use Efavirenz and Amprenivir you need to add nelfinavir (1250mg BID) indinavir (1200 mg BID) or ritonavir (100mg BID).
Abstract 691 (Reid et al): HIV-2 is resistant to AZT and thus AZT cannot be used to treat HIV-2-infected persons. These findings underscore the importance of developing new drugs specific for HIV-2 and indicate that the antiviral activity of AZT may not be as broad as previously thought.
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