Zidovudine pharmacokinetics

Zidovudine Pharmacokinetic Parameters in Fasting Aduit Patients... 

Zidovudine Pharmacokinetics Parameters in Patients with Severe... 

TABLE 23.2 Zidovudine Pharmacokinetic Parameters for Various Age Groups ... 

Mirochnick M, Capparelli E, Dankner W, Sperling RS, vanDyke R, Spec tor SA. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 1998 42 808-12. 

Toffoli G, Errante D, Corona G, Vaccher E, Bertola A, Robieux I, Aita P, Sorio R, Tirelli Lf, Boiocchi M. Interactions of antineoplastic chemotherapy with zidovudine pharmacokinetics in patients with HIV-related neoplasms. Chemotherapy 1999 45(6) 418-28. 

DC Mays, KF Dixon, A Balboa, LJ Pawluk, MR Bauer, S Nawoot, N Gerber. A nonprimate animal model applicable to zidovudine pharmacokinetics in humans Inhibition of glucuronidation and renal excretion of zidovudine by probenecid in rats. J Pharm Exp Ther 259 1261, 1991. 

Probenecid but not cidofovir alters zidovudine pharmacokinetics such that zidovudine doses should be reduced when probenecid is present, as should the doses of drugs similarly affected by probenecid fe.g., /i-lactam antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], acyclovir, lorazepam, furosemide, methotrexate, theophylline, and rifampin). Concurrent nephrotoxic agents are contraindicated, and an interval of 1 week before beginning cidofovir treatment is recommended after prior exposure to aminoglycosides, intravenous pentamidine, amphotericin foscamet, NSAIDs, or contrast dye. Cidofovir and oral ganciclovir in combination are poorly tolerated at full doses. 

Pyrimethamine does not appear to alter zidovudine pharmacokinetics, and zidovudine does not appear to alter the prophylactic efficacy of sulfadoxine/pyrimethamine for toxoplasmosis. The combination of pyrimethamine and zidovudine may increase the risk of myelosuppression. 

Only minimal changes in zidovudine pharmacokinetics were seen when 12 HIV-positive patients taking zidovudine 400 mg to 1 g daily were given a single 500-mg dose of famciclovir. ... 

In vitro data suggest that the altered zidovudine pharmacokinetics may, in part, occur because fluconazole inhibits zidovudine glucuronidation. ... 

Sahai J, Gallicano K, Pakuts A, Cameron DW. Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human deficiency virus. J Infect Dis (1994) 169,1103-7. 

Diaz C, Yogev R, Rodriguez J, Rege A, George W, Lertora J. ACTG-153 Zidovudine pharmacokinetics when used in combination with interferon alpha. Intersci Corf Antimicrob Agents Chemother( 99A) 34, 79. 

MN. Effect of lamivudine on zidovudine pharmacokinetics in asymptomatic HIV-infected individuals. Conf Antimicrob Agents Chetru ter (1994) 34, 83. 

In vitro evidence suggests that chloramphenicol, indometacin and naproxen inhibit the glucuronidation of zidovudine. However, neither indometacin nor naproxen altered zidovudine pharmacokinetics in subsequent clinical studies. Dipyridamole did not alter zidovudine pharmacokinetics. 

Barry M, Howe J, Back D, Breckenridge A, Brettle R, Mitchell R, Beeching NJ, Nye FJ. The effects of indomethacin and naproxen on zidovudine pharmacokinetics. BrJ Clin Pharmacol (1993) 36, 82-5. 

Hendrix CW, Flexner C, Szebeni J, Kuwahara S, Pennypacker S, Weinstein JN, Lietman PS. Effect of dip3 damole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects. Antimicrob Agents Chemo er (1994) 38,1036 0. 

An in vitro study using human liver microsomes found that ethinylestradiol inhibited the glucuronidation of zidovudine by 50% or more, suggesting that ethinyloestradiol may increase the effects and toxicity of zidovudine. However, note that other drugs that had a similar effect in vitro did not alter zidovudine pharmacokinetics in subsequent clinical studies, see NRTIs Zidovudine + Drugs that inhibit glucuronidation , p.808. Further study is needed. 

Pharmacology Lamivudine/zidovudine combination tablets contain 2 synthetic nucleoside analog reverse transcriptase inhibitors with activity against HIV. Lamivudine in combination with zidovudine has exhibited synergistic antiretroviral activity. Refer to lamivudine and zidovudine individual monographs. Pharmacokinetics One combination lamivudine/zidovudine (150/300 mg) tablet is bioequivalent to a 150 mg lamivudine tablet plus a 300 mg zidovudine tablet. 

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. 

Saag MS, Sommadossi JP, Rainey D, Myers M, Cort S, Hall D, et al. A pharmacokinetic and antiretroviral activity study of nevirapine in combination with zidovudine plus zalcitabine (ZDV/ddC), zidovudine plus didanosine (ZDV/ddI), or didanosine (ddl) Alone. In The First National Conference on Human Retroviruses and Related Infections, Washington D.C., 1993 102. 

Watts DH, Brown ZA, Tartaglione T, Burchett SK, et al. 1991. Pharmacokinetic disposition of zidovudine during pregnancy. J Infect Dis. 163 226-232. 

Lertora JJ, Rege AB, Greenspan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1994 56(3) 272-278. 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (zidovudine) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and val-proic acid. Antimicrob Agents Chemother 1998 42 1592-1596. 

Stahle L, Guzenda E, Ljungdahl-Stahle E (1993) Pharmacokinetics and extracellular distribution to blood, brain, and muscle of alovudine (3 -Fluorothymidine) and zidovudine in the rat studied by microdialysis. / AIDS 36 435-439. 

The pharmacokinetic parameters for zidovudine in various age groups are presented in Table 23.2 (4-7). Newborns cleared zidovudine more slowly than did children and adults, and the clearance in preterm newborns is slower than in the full-term infants. Zidovudine clearance rapidly increases over the first few weeks of life, consistent with the up-regulation of glucuronidation pathways in newborns after birth, and by 2 weeks of age approaches values in older children and adults. In addition, the extent of zidovudine absorption (F) in newborns at 14 days of age is higher than in older children, presumably because of reduced first-pass metabolism. Based on these studies, a safe and potentially effective dose of zidovudine was defined for term and preterm newborns (6-8). 

Balls F, Pizzo P, Eddy J, Wilfert C, McKinney R, Scott G, Murphy RF, Jaronsinski PF, Falloon J, Poplack DG. Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. J Pediatr 1989 114 880Hl. 

O Sullivan MJ, Boyer PJ, Scott GB, Parks PW, Weller S, Blum R, Balsley J, Bryson YJ. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants Phase I Acquired Immunodeficiency Syndrome Clinical Trial Group Study (protocol 082) Zidovudine Collaborative Working Group. Am J Obstet Gynecol 1993 168 1510-6. 

Pharmacokinetics. Zidovudine is well absorbed from the gastrointestinal tract (it is available as capsules and syrup) and is rapidly cleared from the plasma (t) 1 h) concentrations in CSF are approximately half those in plasma. It is also available i.v. for patients temporarily imable to take oral medications. The drug is mainly metabolically inactivated, but 20% is excreted unchanged by the kidney. 

Mentre, F. Escolano, S. Diquet, B. GoUnard, J.L. Mallet, A. Clinical pharmacokinetics of zidovudine inter and intraindividual variability and relationship to long-term efficacy and toxicity. Eur. J. Clin. Pharmacol 1993,45 (5), 397-407. 

Clarithromycin reduced the peak concentration and AUC of zidovudine at steady state by about 12% (32), possibly as a result of reduced zidovudine absorption (62). However, if the two drugs were taken at least 2 hours apart, the pharmacokinetics of zidovudine were unaffected. 

Polis M, Haneiwich S, Kovacs J, et al. Dose escalation study to determine the safety, maximally tolerated dose and pharmacokinetics of clarithromycin with zidovudine in HIV-infected patients. In Interscience Conference on Antimicrobial Agents and Chemotherapy American Society for Microbiology, 1991. 

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