Abacavir pharmacokinetics

Dose adjustment in hepatic Impairment The recommended dose of abacavir in patients with mild hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily. To enable dose reduction, use abacavir oral solution (10 ml twice daily) to treat these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment therefore, abacavir is contraindicated in these patients. 

Hepatic function impairment The safety, efficacy, and pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic function impairment, therefore abacavir is contraindicated in these patients. 

Pharmacokinetics Following oral administration, abacavir, lamivudine, and zidovudine are rapidly absorbed and extensively distributed. Binding of abacavir to human plasma proteins is about 50% binding of lamivudine and zidovudine to plasma proteins is low. 

The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting patients are summarized below. 

Kumar PN, Sweet DE, McDowell JA, Symonds W, Lou Y, Hetherington S, LaFon S. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 1999 43(3) 603-8. 

S. Weller, K. M. Radomski, U. Lou, and D. S. Stein, Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 44(8) 2052-2060 (2000). 

Pharmacokinetics and clinical uses There is good oral bioavailability, with metabolism via alcohol dehydrogenase and glucuronosyltransferase. Abacavir has been used in combinations with zidovudine and lamivudine. 

A study in 24 EHV-positive patients found that alcohol 0.7 g/kg increased the AUC of a single 600-mg dose of abacavir by 41%. The half-life of abacavir was increased by 26%, from 1.42 to 1.79 hours. The pharmacokinetics of alcohol were not affected by abacavir. Alcohol may inhibit the formation of abacavir carboxylate resulting in a trend towards increased abacavir glucuronide formation and reduced abacavir metabolism. The increase in exposure to abacavir was not considered to be clinically significant, since it is within levels seen in other studies using higher doses, which demonstrated no additional safety concerns at doses of up to three times the recommended daily dose of abacavir. No special precautions therefore appear to be necessary. 

Zidovudine had no effect on methadone levels in one study, but there is one report of a patient requiring a modest increase in methadone dose after starting zidovudine. Similarly case reports describe patients requiring a modest increase in methadone dose after starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didano-sine from the tablet formulation, but not the enteric-coated capsule preparation. Tenofovir, and a single dose of zidovu-dine/lamivudine had no effect on methadone pharmacokinetics. 

Sellers E, Lam R, McDowell J, Corrigan B, Hedayetullah N, Somer G, Kirby L, Kersey K, Yuen G. The pharmacokinetics of abacavir and methadone following coadministiaticn CNAA1012. InUrsci Conf Antimicrd) Agents Chemother 999) 39, 663. 

Falloon J, Piscitelli S, Vogel S, Sadler B, Mitsuya H, KavUck MF, Yoshimura K, Rogers M, LaFon S, Manion DJ, Lane HC, Masur H. Comhination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV) infected patients failing a protease-inhibitor regimen pharmacokinetic drug interactions and antiviral activity. Clin bfect Dis (2000) 30, 313-18. 

A single 150-mg dose of lamivudine was given with abacavir 600 mg to 13 HIV-positive subjects. The pharmacokinetics of abacavir were not significantly affected, but the lamivudine maximum plasma levels and AUC were decreased by 35% and 15%, respectively. These changes were considered to be consistent with a ehange in absorption. The extent of the... 

Wang LH, Chittick GE, McDowell JA. Single-dose pharmacokinetics and safety of abacavir (1592U89), zidovudine, and lamivudine administered alone and in combination in adults with human immunodeficiency virus infection. Antimicrob Agents Chemo ier (1999) 43, 1708-... 

Buffered didanosine decreases the AUC of indinavir, and the drugs shouid be given one hour apart. Buffered didanosine interacts simiiarly with atazanavir. Tipranavir with low-dose ritonavir modestly reduced the AUC of abacavir and zidovudine, and such combinations are not recommended in the UK. The changes in pharmacokinetics seen when giving other combinations of protease inhibitors with NRTIs do not appear to be clinically significant. Protease inhibitors do not affect the intracellular activation of NRTIs. 

Amprenavir A phase I study in HIV-positive patients given amprenavir 900 mg twice daily with abacavir 300 mg twice daily for 3 weeks found that neither drug had any clinically significant effect on the pharmacokinetics of the other. The manufacturer of amprenavir notes that its AUC, and minimum and maximum levels were increased by 29%, 27%, and 47%, respectively, by abacavir, without any change in abaeavir pharmacokinetics, but no dosage adjustments are considered necessary. ... 

Tenofovir increases the levels of didanosine an increased risk of pancreatitis and peripheral neuropathy has been reported, and a high level of treatment failure. There is no pharmacokinetic interaction between tenofovir and abacavir, emtricitabine, lamivudine or stavudine. However, the combination of tenofovir, lamivudine and abacavir was unexpectedly associated with a high level of treatment failure. Triple-NRTI regimens invoiving tenofovir are not recommended, with the possibie exception of tenofovir, lamivudine and zidovudine. 

Kearney BP, Isaacson E, Sayre J, Ebrahimi R, Cheng AK. The pharmacokinetics of abacavir, a purine nucleoside analog, are not affected by tenofovir DF. Intersci CotfAntimicrob Agents... 

McDowell, J.A. Lou, Y. Symonds, W.S. Stein, D.S. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immimodeflciency virus-infected aAwlts, Antimicrob.Agents Chemother., 2000, 44, 2061-2067. 

McDowell, J.A. Chittick, G.E. Ravitch, J.R. Polk, R.E. Kerkering, T.M. Stein, D.S. Pharmacokinetics of abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults a mass balance study, AntimicrobAgents Chemother., 1999, 43, 2855-2861. 

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