Abacavir dosing

Excretion - Of the 99% of the total abacavir dose recovered, 1.2% was excreted unchanged in the urine as abacavir. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life was approximately 1.54 hours. 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

In the broadest sense, genotyping can also be used in proof-of-principle trials and for individualization and modification of dose based on genotype. Associations between genotypes and clinical outcomes can also be explored retrospectively, as was the case for abacavir,20 21 but these are mainly exploratory and would need confirmation in a clinical trial prospectively. An important distinction was made between two types of genome-based enrichment the first type (preferred) is when there is a well-understood, genome-based pathophysiological ability to select responders and nonresponders, and the second type is when genomic-based predictions of differences in response are... 

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. 

Dose adjustment Do not prescribe abacavir/lamivudine to patients requiring dosage adjustment such as those with Ccr less than 50 mL/min, those with hepatic impairment, or those experiencing dose-limiting adverse events. 

Renal function impairment Lamivudine requires dose adjustment in the presence of renal insufficiency abacavir/lamivudine is not recommended for use in patients with Ccr less than 50mL/min. 

Liver function /mpa/rmenf.-Abacavir is contraindicated in patients with moderate to severe hepatic impairment, and dose reduction is required in patients with mild hepatic impairment. Because abacavir/lamivudine is a fixed-dose combination and cannot be dose adjusted, abacavir/lamivudine is contraindicated for patients with hepatic impairment. 

Fixed-dose combination This combination contains fixed doses of 2 nucleoside analogs, abacavir and lamivudine, and should not be administered concomitantly with other abacavir-containing and/or lamivudine-containing products. Hypersensitivity reactions Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir/lamivudine and other abacavir-containing products. 

Lamivudine (3TC, Epivir) is a cytosine nucleoside analogue with activity against HIV-1, HIV-2, and hepatitis B virus. It is approved as part of a multidrug regimen for the therapy of HIV infection in adults and children and has been used for HIV postexposure prophylaxis. Combination products contain lamivudine with either zidovudine (Combivir) or zidovudine and abacavir (Trizivir). The use of low-dose lamivudine in the treatment of chronic hepatitis B is described in Chapter 50. 

Abacavir (Ziagen) is a guanosine nucleoside analogue indicated for the therapy of HIV-1 infection in adults and children. It is used as part of a multidrug regimen and is available in a fixed-dose combination with zidovudine and lamivudine (Trizivir). It is also used for postexposure HIV infection prophylaxis. 

METHADONE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS 1 efficacy of methadone when co-administered with abacavir Uncertain possibly enzyme induction Monitor for opioid withdrawal and consider increasing dose... 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

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. 

Kost RG, Hurley A, Zhang L, Vesanen M, Talal A, Furlan S, Caldwell P, Johnson J, Smiley L, Ho D, Markowitz M. Open-label phase II trial of amprenavir, abacavir, and fixed-dose zidovudine/lamivudine in newly and chronically HIV-l-infected patients. J Acquir Immune Defic Syndr 2001 26(4) 332-9. 

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). 

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. 

The reduction in stavudine levels and the changes in abacavir peak levels with methadone are probably not clinically relevant, but again, further data are required. The reports with abacavir suggest that it would be prudent to monitor methadone dose requirements when this drug is started. Tenofovir does not appear to affect methadone levels. 

A study involving 16 opioid-dependent subjects found that amprenavir 1.2 g twice daily for 10 days decreased the AUCs for both f -methadone (active enantiomer) and 5-methadone (inactive enantiomer) by 13% and 40%, respectively. No clinically significant changes were noted in opioid effects and there was no evidence of opioid withdrawal. However, in another study methadone levels were reduced by 35% (range 28% to 87%) in 5 patients within 17 days of starting to take amprenavir 1.2 g twice daily and abacavir 600 mg twice daily. Two patients reported nausea before their daily methadone dose, which can be a sign of opiate withdrawal. Note that abacavir , (p.l75), may modestly reduce methadone levels, and could therefore have contributed to this effect. 

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... 

A single 300-mg dose of zidovudine was given with abacavir 600 mg to 13 mV-positive subjects. The pharmaeokinetics of abacavir were not significantly affected. The zidovudine maximum plasma level deereased by 20%, but the AUC was unchanged. This ehange is not thought to be elin-ically significant and so no dose alteration would seem neeessaty on eon-current use. These results were eonfirmed in a steady-state study in which 79 mV-positive subjects received 8 weeks of treatment with abacavir 600 mg to 1.8 g daily, in divided doses, and zidovudine 600 mg daily, in divided doses. The triple NRTI eombination of abacavir, lamivudine and zidovudine may also be considered if protease inhibitors or NNRTIs cannot be used. ... 

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. 

Tipranavir with Ritonavir. Tipranavir given with low-dose ritonavir decreased the AUC of abacavir by approximately 40%. The clinical relevance of this reduction has not been established,but it may decrease the efficacy of abacavir. Therefore the UK manufacturer states that the concurrent use of tipranavir and low-dose ritonavir with abacavir is not recommended unless there are no other available NRTIs suitable for patient management. ... 

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