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Zidovudine (azidothymidine AZT)☆
Zidovudine (azidothymidine AZT)☆ D Mondal, Tulane University, New Orleans, LA, United States ã 2016 Elsevier Inc. All rights reserved.
Introduction Basic Chemistry Mechanism of Action Target Name(s) Indications Contraindications Side Effects Human Pharmacokinetics Potency Drug Interactions Pre-Clinical & Clinical Research Combination Therapy Monotherapy Pediatric Patients Prevention of Maternal-Fetal HIV-1 Transmission Resistance References
Name of the clinical form Related names source: EMTREE
Chemical names CAS number
1 2 2 2 2 3 3 3 4 4 4 4 4 5 5 5 5
Zidovudine Azidothymidine; Compound S; Retrovir; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; Zidovudine; Retrovir (trade); AZT (trade); Azidothymidine (trade); 3’ azido 20 ,30 dideoxyribosylthymine; 30 azido 20 ,30 dideoxythymidine; 30 azido 30 deoxythymidine; 30 azidothymidine; AZT; azidodeoxythymidine; azidothymidine; aztec; bio zt; bw a 509 u; bw a509u; bwa509u; retrovir; thymidine,30 azido; thymidine,30 azido 20 ,30 dideoxy; thymidine,30 azido 30 deoxy; zdv 30 -azido-30 -deoxythymidine 30516-87-1
Introduction Zidovudine (AZT) was the first U.S. government-approved treatment for HIV, marketed under the brand name Retrovir [Broder (2009)]. It was the first breakthrough in AIDS therapy, significantly reducing the replication of the virus and leading to clinical and immunologic improvements [Wright (1986)]. It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick injury. Zidovudine is also indicated for the prevention of maternal-fetal HIV-1 transmission. Used by itself in HIV-infected patients, AZT slows HIV replication in patients, but does not stop it entirely. [Jeffries (1989).] HIV may become AZT-resistant over time, and therefore AZT is now usually used in conjunction with other anti-HIV drugs in the combination therapy called highly active antiretroviral therapy (HAART). Monotherapy with AZT is recommended only in the initial management of HIV-1 infected patients. However, combination therapy should be employed in advanced disease. AZT is used in combination therapy with lamuvidine as combivir and with lamuvidine and abacavir as trizvir. Current treatment regimens involve relatively lower dosages of AZT taken just twice a day, almost always as part of HAART, in which AZT is combined with other drugs (known affectionately as “the triple cocktail") in order to prevent the selection of HIV into an AZT-resistant form. [De Clercq (1994), Yarchoan et al. (1988)] It has been demonstrated that AZT causes bone marrow suppression and can exacerbate the manifestations of anemia in HIV-positive individuals. Early long-term higher-dose therapy with AZT is associated with side effects including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the g-DNA polymerase in some cell mitochondria,[32] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[33] ☆ Change History: January 2016. D. Mondal updated Abstract, extensively changed the content format, included new research findings, and included new references.
Reference Module in Biomedical Sciences
http://dx.doi.org/10.1016/B978-0-12-801238-3.99390-5
1
2
Zidovudine (azidothymidine AZT)
Basic Chemistry AZT is a deoxythymidine analog. AZT crystallizes into an asymmetric nucleated monoclinic salt structure.
Chemical structure Structure
Comments Chemical formula Properties Physical properties Molecular weight Solubility
AZT is a synthetic nucleoside analogue of the naturally occurring nucleoside thymidine. C10 H13 N5 O4 White to beige, odorless, crystalline solid. 267.244 25.0 mg/ml in water at 25 C [Budavari (1996)]
Mechanism of Action It is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class. AZT inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming. Within the cells, AZT is converted to the active metabolite, zidovudine 50 -triphosphate (AztTP), by the sequential action of the cellular enzymes. AztTP inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 50 -triphosphate (dTTP), and by its incorporation into viral DN A. The lack of 30 -OH group in the incorporated nucleoside analogue prevents the formation of the 50 to 30 phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated.
Target Name(s)
•
HIV reverse transcriptase enzyme
Indications AZT in combination with other antiretroviral agents is used in the treatment of HIV. It is indicated for the prevention of maternalfetal HIV transmission. It is also used as a prophylaxis in case of occupational exposure. The oral form is administered during pregnancy and the i.v. infusion is administered during labor and delivery. Dosing Information:
• • • • • • • • • •
Adults: AZT is used in monotherapy during initial treatment of patients with CD4 cell count <500/cu. Mm. For the treatment of HIV infection in adults, the recommended dose is 1 mg/kg IV infused over 1 h 5 to 6 times a day. The patient should be switched to oral therapy as soon as possible. 600 mg/day ORALLY in divided doses. HIV infection: 1 mg/kg/dose IV 5 to 6 times a day. Maternal-fetal HIV-transmission: For prevention of HIV-transmission during delivery as part of a regimen. [Connor et al. (1994)] The indication is based on a dosing regimen that include, antepartum therapy of HIV-1 infected mothers, intrapartum therapy of HIV-1 infected mothers or post-partum therapy of HIV-1 exposed neonate Maternal Dosing: In HIV-infected women with HIV RNA levels greater than 400 copies/mL (or unknown HIV RNA) near delivery, regardless of antiretroviral therapy, the recommended regimen during labor and delivery (intrapartum) is zidovudine 2 mg/kg IV infused over 1 hour, followed by a continuous infusion of 1 mg/kg/hr until the umbilical cord is clamped. During pregnancy (greater than 14 week of pregnancy), 100 mg orally 5 times daily until the start of labor. A regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, i.v. zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of mother-to-newborn transmission of HIV by up to 23% (Safrin, 2012).
Zidovudine (azidothymidine AZT)
• •
3
Neonatal Guideline Dosing: The full-term neonate (gestational age of 35 weeks or greater) should receive zidovudine 4 mg/kg orally twice daily for 6 weeks; initiate within 6–12 h of birth. Preterm neonatal dosing for infants with a gestational age less than 35 weeks is 2 mg/kg orally every 12 h.
Contraindications
• •
Allergic reactions to AZT Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis steatosis have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals.
Side Effects
•
Anemia and granulocyotpenia, myopathy, lactic acidosis, pancreatitis. Hematologic Toxicity/Bone Marrow Suppression: Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1000 cells/mm3 or hemoglobin < 9.5 g/dL. Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with zidovudine. Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Human Pharmacokinetics
• •
Combination therapy: With another nucleoside, one or two non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors during highly active anti-retroviral therapy (HAART). Also administered intravenously (i.v.) for the management of patients with AIDS and a history of pneumocystis carinii pneumonia (PCP) or a <200/cu. Mm. CD4 count.
Upon oral administration AZT is rapidly absorbed. The oral form includes tablets, capsules, and syrup. The tablets contain 300 mg, the capsules contain 100 mg, and 5 mL of syrup contains about 50 mg AZT. Well absorbed from the gut & distributed to most body tissues. Serum half-life is 1 h and intracellular half-life is 3.3 h. AZT is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance is reduced by 50% in uremic patients and toxicity may increase in patients with advanced hepatic insufficiency. Intravenous infusion is indicated for adult patients who have a history of Pnuemocystis carinii pneumonia (PCP) or an absolute CD4 lymphocyte count of < 200/mm3 in the peripheral blood. Since AZT is primarily eliminated by hepatic metabolism, patients with hepatic impairment have higher plasma levels of AZT. Pharmacokinetic Properties: [Physician’s Desk Reference (2000)]
Absorption Bioavailability Distribution Volume of distribution Plasma protein binding Metabolism Plasma half-life Bio half-life Clearance Routes of elimination
Value
Units
Prep. and route of admin.
Reference
64
%
Oral
1.6 <38
l/kg %
Oral/i.v. Infusion Oral/i.v. Infusion
Physician’s Desk Reference (2000) Physician’s Desk Reference (2000)
0.5–3
h
Oral
Physician’s Desk Reference (2000)
1.6; 0.34 l/h/kg; l/h/kg Oral/i.v. Infusion; oral/i.v. Infusion AZT is primarily eliminated by hepatic metabolism.
Physician’s Desk Reference (2000)
Comments
Systemic; renal
4
Zidovudine (azidothymidine AZT)
Potency
Organ/ Tissue
Prep. and route of admin.
Value
Units
Mice LD50
3568
mg/kg
Orally
LD50
3062
mg/kg
Orally
Rats LD50
3084
mg/kg
Orally
LD50
3063
mg/kg
Orally
Cell line/type
Effects
Exp. end point
Reference
Comments
Budavari (1996) Budavari (1996)
Male
Budavari (1996) Budavari (1996)
Male
Female
Female
Drug Interactions
Agent name Antiretroviral agents Ganciclovir Interferon-alpha
• • •
Mode of interaction Antagonistic interactions Bone marrow suppression Bone marrow suppression
DO NOT coadminister with stavudine since zidovudine may reduce the phosphorylation of stavudine. Avoid concurrent use of myelosuppressive drugs (eg, ganciclovir, ribavirin) Patients should be cautioned about the use of other medications, including ganciclovir, interferon alfa and ribavirin, which may exacerbate the toxicity of zidovudine.
Pre-Clinical & Clinical Research Studies to assess the carcinogenicity, teratogenicity, and fertility impairment have been performed in rats, mice, and rabbits. In both mice and rats at the highest dose, there was development of neoplasm and carcinomas Physician’s Desk Reference (2000). At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 h Physician’s Desk Reference (2000). Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity. Mouse oocytes treated with AZT showed dose-dependent reduction in blastocyst formation Drug Facts and Comparisons (2001a), Drug Facts and Comparisons (2001b).
Combination Therapy
•
Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
Monotherapy
•
In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with zidovudine, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. A survival benefit for monotherapy with zidovudine was not demonstrated in the latter two studies. Subsequent studies showed that the clinical benefit of monotherapy with zidovudine was time limited.
Zidovudine (azidothymidine AZT)
5
Pediatric Patients
•
ACTG 300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR® plus zidovudine to didanosine monotherapy.
Prevention of Maternal-Fetal HIV-1 Transmission
•
The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, doubleblind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4 + cell counts of 200–1818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to zidovudine. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants.
Resistance
•
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of substitutions conferring resistance to zidovudine.
References Broder S (2009) The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 85(1): 1–2. http://dx.doi.org/10.1016/j.antiviral.2009.10.002. PMC 2815149. PMID 20018391. Connor E, Sperling R, Gelber R, Kiselev P, Scott G, O’Sullivan M, VanDyke R, Bey M, Shearer W, and Jacobson R (1994) Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N. Engl. J. Med. 331(18): 1173–1180. http://dx.doi.org/ 10.1056/NEJM199411033311801. PMID 7935654. De Clercq E (1994) HIV resistance to reverse transcriptase inhibitors. Biochem. Pharmacol. 47(2): 155–169. http://dx.doi.org/10.1016/0006-2952(94)90001-9. PMID 7508227. Jeffries DJ (1989) Zidovudine resistant HIV. BMJ (Clinical research ed.) 298(6681): 1132–1133. http://dx.doi.org/10.1136/bmj.298.6681.1131. PMID 2500164. Wright K (1986) AIDS therapy: first tentative signs of therapeutic promise. Nature 323(6086): 283. http://dx.doi.org/10.1038/323283a0. PMID 3463865. Yarchoan R, Mitsuya H, and Broder S (1988) AIDS therapies. Sci. Am. 259(4): 110–119. http://dx.doi.org/10.1038/scientificamerican1088-110. PMID 3072667. Book Citations Budavari S (1996) The merck index, 12th ed. NJ: Merck Research Laboratories Whitehouse Station. Burnham TH, Bell WL, and Schweain SL (2001) Antiretroviral agents. Drug Facts and Comparisons, 5th ed. Missouri: Wolters Kluwer Company St. Louis pp. 881–884. Cada DJ (2001) Antiviral agents, Drug Facts and Comparisons, 5th ed. Missouri: Wolters Kluwer Company St. Louis846–848. Safrin S (2012) Antiviral Agents (Chapter 49). In: Katzung BG, Masters SB, and Trevor AJ (eds.) Basic and Clinical Pharmacology, 12th edn. McGraw-Hill/Lange, (Access-Medicine). Sifton DW (2000) Physicians’ desk reference, 54th ed. New Jersey: Medical Economics Company Montvale.
Relevant Websites http://www.rxlist.com/retrovir-drug.htm.
Introduction Basic Chemistry Mechanism of Action Target Name(s) Indications Contraindications Side Effects Human Pharmacokinetics Potency Drug Interactions Pre-Clinical & Clinical Research Combination Therapy Monotherapy Pediatric Patients Prevention of Maternal-Fetal HIV-1 Transmission Resistance References
Name of the clinical form Related names source: EMTREE
Chemical names CAS number
1 2 2 2 2 3 3 3 4 4 4 4 4 5 5 5 5
Zidovudine Azidothymidine; Compound S; Retrovir; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; 1-((2R,4S,5S)-4-Azido-5-hydroxymethyl-tetrahydro-furan-2-yl)5-methyl-1H-pyrimidine-2,4-dione; Zidovudine; Retrovir (trade); AZT (trade); Azidothymidine (trade); 3’ azido 20 ,30 dideoxyribosylthymine; 30 azido 20 ,30 dideoxythymidine; 30 azido 30 deoxythymidine; 30 azidothymidine; AZT; azidodeoxythymidine; azidothymidine; aztec; bio zt; bw a 509 u; bw a509u; bwa509u; retrovir; thymidine,30 azido; thymidine,30 azido 20 ,30 dideoxy; thymidine,30 azido 30 deoxy; zdv 30 -azido-30 -deoxythymidine 30516-87-1
Introduction Zidovudine (AZT) was the first U.S. government-approved treatment for HIV, marketed under the brand name Retrovir [Broder (2009)]. It was the first breakthrough in AIDS therapy, significantly reducing the replication of the virus and leading to clinical and immunologic improvements [Wright (1986)]. It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick injury. Zidovudine is also indicated for the prevention of maternal-fetal HIV-1 transmission. Used by itself in HIV-infected patients, AZT slows HIV replication in patients, but does not stop it entirely. [Jeffries (1989).] HIV may become AZT-resistant over time, and therefore AZT is now usually used in conjunction with other anti-HIV drugs in the combination therapy called highly active antiretroviral therapy (HAART). Monotherapy with AZT is recommended only in the initial management of HIV-1 infected patients. However, combination therapy should be employed in advanced disease. AZT is used in combination therapy with lamuvidine as combivir and with lamuvidine and abacavir as trizvir. Current treatment regimens involve relatively lower dosages of AZT taken just twice a day, almost always as part of HAART, in which AZT is combined with other drugs (known affectionately as “the triple cocktail") in order to prevent the selection of HIV into an AZT-resistant form. [De Clercq (1994), Yarchoan et al. (1988)] It has been demonstrated that AZT causes bone marrow suppression and can exacerbate the manifestations of anemia in HIV-positive individuals. Early long-term higher-dose therapy with AZT is associated with side effects including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the g-DNA polymerase in some cell mitochondria,[32] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells.[33] ☆ Change History: January 2016. D. Mondal updated Abstract, extensively changed the content format, included new research findings, and included new references.
Reference Module in Biomedical Sciences
http://dx.doi.org/10.1016/B978-0-12-801238-3.99390-5
1
2
Zidovudine (azidothymidine AZT)
Basic Chemistry AZT is a deoxythymidine analog. AZT crystallizes into an asymmetric nucleated monoclinic salt structure.
Chemical structure Structure
Comments Chemical formula Properties Physical properties Molecular weight Solubility
AZT is a synthetic nucleoside analogue of the naturally occurring nucleoside thymidine. C10 H13 N5 O4 White to beige, odorless, crystalline solid. 267.244 25.0 mg/ml in water at 25 C [Budavari (1996)]
Mechanism of Action It is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class. AZT inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming. Within the cells, AZT is converted to the active metabolite, zidovudine 50 -triphosphate (AztTP), by the sequential action of the cellular enzymes. AztTP inhibits the activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine 50 -triphosphate (dTTP), and by its incorporation into viral DN A. The lack of 30 -OH group in the incorporated nucleoside analogue prevents the formation of the 50 to 30 phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated.
Target Name(s)
•
HIV reverse transcriptase enzyme
Indications AZT in combination with other antiretroviral agents is used in the treatment of HIV. It is indicated for the prevention of maternalfetal HIV transmission. It is also used as a prophylaxis in case of occupational exposure. The oral form is administered during pregnancy and the i.v. infusion is administered during labor and delivery. Dosing Information:
• • • • • • • • • •
Adults: AZT is used in monotherapy during initial treatment of patients with CD4 cell count <500/cu. Mm. For the treatment of HIV infection in adults, the recommended dose is 1 mg/kg IV infused over 1 h 5 to 6 times a day. The patient should be switched to oral therapy as soon as possible. 600 mg/day ORALLY in divided doses. HIV infection: 1 mg/kg/dose IV 5 to 6 times a day. Maternal-fetal HIV-transmission: For prevention of HIV-transmission during delivery as part of a regimen. [Connor et al. (1994)] The indication is based on a dosing regimen that include, antepartum therapy of HIV-1 infected mothers, intrapartum therapy of HIV-1 infected mothers or post-partum therapy of HIV-1 exposed neonate Maternal Dosing: In HIV-infected women with HIV RNA levels greater than 400 copies/mL (or unknown HIV RNA) near delivery, regardless of antiretroviral therapy, the recommended regimen during labor and delivery (intrapartum) is zidovudine 2 mg/kg IV infused over 1 hour, followed by a continuous infusion of 1 mg/kg/hr until the umbilical cord is clamped. During pregnancy (greater than 14 week of pregnancy), 100 mg orally 5 times daily until the start of labor. A regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, i.v. zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of mother-to-newborn transmission of HIV by up to 23% (Safrin, 2012).
Zidovudine (azidothymidine AZT)
• •
3
Neonatal Guideline Dosing: The full-term neonate (gestational age of 35 weeks or greater) should receive zidovudine 4 mg/kg orally twice daily for 6 weeks; initiate within 6–12 h of birth. Preterm neonatal dosing for infants with a gestational age less than 35 weeks is 2 mg/kg orally every 12 h.
Contraindications
• •
Allergic reactions to AZT Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis steatosis have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals.
Side Effects
•
Anemia and granulocyotpenia, myopathy, lactic acidosis, pancreatitis. Hematologic Toxicity/Bone Marrow Suppression: Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1000 cells/mm3 or hemoglobin < 9.5 g/dL. Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with zidovudine. Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Human Pharmacokinetics
• •
Combination therapy: With another nucleoside, one or two non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors during highly active anti-retroviral therapy (HAART). Also administered intravenously (i.v.) for the management of patients with AIDS and a history of pneumocystis carinii pneumonia (PCP) or a <200/cu. Mm. CD4 count.
Upon oral administration AZT is rapidly absorbed. The oral form includes tablets, capsules, and syrup. The tablets contain 300 mg, the capsules contain 100 mg, and 5 mL of syrup contains about 50 mg AZT. Well absorbed from the gut & distributed to most body tissues. Serum half-life is 1 h and intracellular half-life is 3.3 h. AZT is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance is reduced by 50% in uremic patients and toxicity may increase in patients with advanced hepatic insufficiency. Intravenous infusion is indicated for adult patients who have a history of Pnuemocystis carinii pneumonia (PCP) or an absolute CD4 lymphocyte count of < 200/mm3 in the peripheral blood. Since AZT is primarily eliminated by hepatic metabolism, patients with hepatic impairment have higher plasma levels of AZT. Pharmacokinetic Properties: [Physician’s Desk Reference (2000)]
Absorption Bioavailability Distribution Volume of distribution Plasma protein binding Metabolism Plasma half-life Bio half-life Clearance Routes of elimination
Value
Units
Prep. and route of admin.
Reference
64
%
Oral
1.6 <38
l/kg %
Oral/i.v. Infusion Oral/i.v. Infusion
Physician’s Desk Reference (2000) Physician’s Desk Reference (2000)
0.5–3
h
Oral
Physician’s Desk Reference (2000)
1.6; 0.34 l/h/kg; l/h/kg Oral/i.v. Infusion; oral/i.v. Infusion AZT is primarily eliminated by hepatic metabolism.
Physician’s Desk Reference (2000)
Comments
Systemic; renal
4
Zidovudine (azidothymidine AZT)
Potency
Organ/ Tissue
Prep. and route of admin.
Value
Units
Mice LD50
3568
mg/kg
Orally
LD50
3062
mg/kg
Orally
Rats LD50
3084
mg/kg
Orally
LD50
3063
mg/kg
Orally
Cell line/type
Effects
Exp. end point
Reference
Comments
Budavari (1996) Budavari (1996)
Male
Budavari (1996) Budavari (1996)
Male
Female
Female
Drug Interactions
Agent name Antiretroviral agents Ganciclovir Interferon-alpha
• • •
Mode of interaction Antagonistic interactions Bone marrow suppression Bone marrow suppression
DO NOT coadminister with stavudine since zidovudine may reduce the phosphorylation of stavudine. Avoid concurrent use of myelosuppressive drugs (eg, ganciclovir, ribavirin) Patients should be cautioned about the use of other medications, including ganciclovir, interferon alfa and ribavirin, which may exacerbate the toxicity of zidovudine.
Pre-Clinical & Clinical Research Studies to assess the carcinogenicity, teratogenicity, and fertility impairment have been performed in rats, mice, and rabbits. In both mice and rats at the highest dose, there was development of neoplasm and carcinomas Physician’s Desk Reference (2000). At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 h Physician’s Desk Reference (2000). Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity. Mouse oocytes treated with AZT showed dose-dependent reduction in blastocyst formation Drug Facts and Comparisons (2001a), Drug Facts and Comparisons (2001b).
Combination Therapy
•
Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
Monotherapy
•
In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with zidovudine, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. A survival benefit for monotherapy with zidovudine was not demonstrated in the latter two studies. Subsequent studies showed that the clinical benefit of monotherapy with zidovudine was time limited.
Zidovudine (azidothymidine AZT)
5
Pediatric Patients
•
ACTG 300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR® plus zidovudine to didanosine monotherapy.
Prevention of Maternal-Fetal HIV-1 Transmission
•
The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, doubleblind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4 + cell counts of 200–1818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to zidovudine. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants.
Resistance
•
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of substitutions conferring resistance to zidovudine.
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Relevant Websites http://www.rxlist.com/retrovir-drug.htm.