A20.2.8 Antiviral agents
Zidovudine, a thymidine nucleoside analogue, is an antiviral medicine with in vitro activity against retroviruses, such as the Human Immunodeficiency Virus (HIV) and the Human T lymphotropic virus (HTLV)-I. Following diffusion into both infected and uninfected host cells, zidovudine is phosphorylated to the monophosphate derivative by cellular thymidine kinase. The phosphorylation of zidovudine-monophosphate to the diphosphate derivative and to the zidovudine-triphosphate is in turn catalysed by cellular thymidylate kinase and unspecific kinases, respectively. Zidovudine-triphosphate is a competitive inhibitor of, and a substrate for, reverse transcriptase with respect to the thymidine triphosphate (TTP) nucleotide. The incorporation of zidovudine-triphosphate into the proviral DNA chain blocks further chain formation and results in chain termination. Zidovudine-triphosphate has greater affinity (approximately 100-fold) for HIV reverse transcriptase than for human DNA polymerase alpha. Combination therapy with lamivudine.
Zidovudine monotherapy leads to development of in vitro and in vivo resistance to zidovudine.
Zidovudine has been shown to act additively or synergistically with other anti-HIV agents, inhibiting the replication of HIV in cell culture. Additive or synergistic activity in cell culture has been demonstrated in medicine combination studies of zidovudine with indinavir, zalcitabine, didanosine, delaviridine, lamivudine, saquinavir, ritonavir, nevirapine, and interferon-alpha.
In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they acquire resistance to lamivudine.
Zidovudine is well absorbed from the gut, and oral bioavailability is approximately 60 to 70%. Absorption varies in HIV-infected patients and is retarded after food intake. Cerebrospinal fluid concentrations vary but average approximately 53% of those in plasma in adults, and 24% of those in plasma in children.
The plasma elimination half-life is approximately 0,9 to 1,5 hours. Zidovudine undergoes first-pass hepatic metabolism and is converted to its 5′-O-glucuronide metabolite, which has a similar plasma elimination half-life, but lacks anti-HIV activity. The recovery of zidovudine and its glucuronide metabolite in urine, after oral administration, averages 14% and 75%, respectively. Renal clearance involves both glomerular filtration and tubular secretion. Two- to three-fold increases in plasma levels and plasma elimination half-life occur in liver cirrhosis. There are no clinically significant pharmacokinetic interactions when zidovudine is given concomitantly with the following antiretroviral medicines:
– Nucleoside reverse transcriptase inhibitors (NRTIs) (zalcitabine, didanosine and abacavir)
– Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine and efavirenz)
– Protease inhibitors
(indinavir sulphate, saquinavir mesylate, ritonavir, amprenavir, and nelfinavir)
Pharmacokinetics in children :
Zidovudine clearance is significantly reduced in children less than one month of age. In children over the age of five months, the pharmacokinetic profile of zidovudine is similar to that in adults.
ASPEN ZIDOVUDINE SYRUP is indicated in combination with other antiretroviral agents for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, children and mothers who are not breast-feeding.
Patients should be warned about the concomitant use of self-administered medicines (see Interactions).
PATIENTS SHOULD BE ADVISED THAT ASPEN ZIDOVUDINE SYRUP THERAPY HAS NOT BEEN SHOWN TO REDUCE THE RISK OF TRANSMISSION OF HIV TO OTHERS THROUGH SEXUAL CONTACT OR BLOOD CONTAMINATION.
Pregnant women considering the use of ASPEN ZIDOVUDINE SYRUP during pregnancy for prevention of HIV transmission to their infants should–be advised thattransmission might still occur despite therapy.
ASPEN ZIDOVUDINE SYRUP is not a cure for HIV infection and patients remain at risk of developing illnesses associated with immune suppression, including opportunistic infections and neoplasms.
In patients with early HIV disease on long-term treatment, the risk of lymphoma development is unknown as data on the development of neoplasms, including lymphomas are limited.
Patients receiving combination therapy may also continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close observation by medical practitioners experienced in the treatment of patients with HIV-associated diseases.
As zidovudine is primarily eliminated by hepatic conjugation to its inactive glucuronidated metabolite, medicines that are primarily eliminated by hepatic metabolism, especially by glucuronidation, may have the potential to inhibit the metabolism of ASPEN ZIDOVUDINE SYRUP. The interactions listed below, though not exhaustive, are representative of the classes of medicines where caution should be exercised: