Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Stavudine (d4T, Zerit)

      • Stavudine (Zerit, d4T) is another example of a pyrimidine nucleoside analog.

      • Stavudine is an "prodrug" in that it must undergo conversion to the triphosphate form which is required for activity against HIV-1.⁴ 

      • As described in the figure below, stavudine differs from thymidine by replacement of the 3'-hydroxyl group with a hydrogen atom and by a double bond in the 2'-, 3'-positions on the deoxyribose ring structure.⁴ 

        •  

          Structural Comparison Between Thymidine and Stavudine⁶

          Thymidine

          Stavudine (Zerit)

           

      • Stavudine, as the triphosphate, inhibits reverse transcriptase enzyme activity both in HIV -1 and in HIV-2 based on in vitro assays.¹

        • In a manner roughly similar to zidovudine, stavudine is initially phosphorylated by thymidine kinase to the 5'-monophosphate which is subsequently phosphorylated by thymidylate kinase to the diphosphate form and then further phosphorylated by a nucleoside diphosphate kinase to the active drug, stavudine 5'-triphosphate.

        • By contrast to zidovudine monophosphate, stavudine monophosphate does not appear to accumulate in the cell; therefore, the rate-limiting step for stavudine activation is likely the initial formation of the monophosphate form.

        • Comparable to zidovudine, stavudine exhibits highest potency in activated cells, i.e. during cell division perhaps because thymidine kinase appears to be a S-phase-specific enzyme.^1,10

          •  

            Schematic of the Cell Cycle

            M = Mitosis:  "Cell growing stops at this stage and cellular energy is focused on the orderly division into two daughter cells.  A checkpoint in the middle of mitosis (Metaphase checkpoint) ensures that the cell is ready to complete cell division." I = Interphase G1 = Gap1 phase: Part of Interphase-"Cells increase in size in Gap 1.  The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis." G2 = Gap2 phase:  Part of interphase- "During the gap between DNA synthesis and mitosis, the cell will continue to grow.  The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide." S = Synthesis phase:  "DNA replication occurs during this phase." G0 = Resting phase; "A resting phase where the cell has left the cycle and has stopped dividing." Wheeler R Schematic representation of the cell cycle. 2006 http://commons.wikimedia.org/wiki/File:Cell_Cycle_2-2.svg http://en.wikipedia.org/wiki/Cell_cycle

         

        • Mutations and Stavudine Resistance:

          • As described for zidovudine, the mutational pattern at reverse transcriptase codons conferring stavudine drug resistance has been described at codons:^1,9,11 

            • 41 (leucine for methionine)

            • 44

            • 67 (asparagine for aspartate)

            • 70 (arginine for lysine)

            • 210 (tryptophan for leucine)

            • 215 (tyrosine or phenylalanine for threonine), and

            • 219 (glutamine or glutamate for lysine).

          • Mutational resistance clusters (M41L (leucine for methionine, K70R (arginine for lysine), and T215Y (tyrosine for threonine)) appears to account for about 40% % of patients failing to respond to stavudine.¹ 

          • Thymidine analogue mutations (TAMS) conferring resistance to stavudine and zidovudine promote pyrophosphorolysis as a means of excision of incorporated triphosphate anabolites (incorporated antiretroviral-drug triphosphates that otherwise would result in chain termination).^1,12 

          • Stavudine resistance mutations develop and accumulate slowly and cross-resistance to several nucleoside analogues is noted with prolonged treatment.

            • A particular mutation at codon 69 (T69S serine for threonine)) along with a 2-amino acid insertion induces cross-resistance to contemporary nucleoside and nucleotide analogues.^1,9

        • Pharmacokinetics:¹

          • Stavudine, following oral administration, is well absorbed with bioavailability averaging between 82% and 100% in clinical studies.¹³ 

          • Although the absorption rate of stavudine was diminished by co-administration with food, the area under the curve (AUC) was unaffected.¹³  

            • This result suggests that the total absorption is similar to that observed in fasting individuals.

              • As a result, stavudine may be administered with or without food.

          • Generally, stavudine doses may not require adjustment for total patient body weight, for patients weighing between 40 and 100 kg.

            • However, contemporary recommendations promote standard dose reduction when patients weigh <60 kg.¹³  

          • Dosage change may also be appropriate in those patients with renal insufficiency.^1,14  

            • The basis for dosage adjustment is that about 40% of the dose is excreted without change in the urine.

            • Patients with renal failure may be more likely to experience peripheral neuropathy, a side effect occurring in about 15% to 21% of stavudine-treated patients who do not have kidney dysfunction.¹⁴

        • Adverse Effects:¹

          • The most frequently observed and serious stavudine toxic effect is peripheral neuropathy.¹ 

            • With the current recommended dose (40 mg twice a day) the neuropathy incidence is about 10%.

            • Mechanisms including inhibition of DNA polymerase-γ may be responsible.¹ 

              • Factors that predispose to peripheral neuropathy following stavudine include higher stavudine doses and the presence of stavudine-independent HIV-related neuropathy.

                • Additionally, increased risk of stavudine-mediated peripheral neuropathy may occur in patients receiving other neurotoxic drugs, including didanosine, vincristine, isoniazid or ribavirin.^1,7 

                • Stavudine may also be associated with a progressive motor neuropathy that may ultimately include respiratory failure.^1,15 

                  • This disorder has been described as similar to Guillain-Barré syndrome.

            • Comparative tolerability of stavudine and zidovudine¹³  

              "Comparative tolerability of stavudine (STV) and zidovudine (ZDV). "Incidence per 100 patient-years of adverse events that occurred significantly more frequently in patients who received either stavudine 40 mg twice daily (n=412) or zidovudine 200 mg three times daily (n=402) in a double blind randomised trail of monotherapy. "All patients had previously received at least 6 months of zidovudine monotherapy. "*p < 0.05, **p <0,01m ***p=0.0001 vs STV; † p<0.04, ‡=p-.01 vs ZDV." Stavudine (Zerit™), also known as D4T.  Final results of the study BMS-019 (AI455-019) Phase III comparative trial.  Bristol-Myers Squibb Company, Princeton, New Jersey, USA, 1995. [second sourced from reference 13]

          • Considering the nucleoside analogues, stavudine administration is the drug most associated with lipoatrophy (Fat wasting).¹

            • The underlying mechanism of action remains to be determined; however mitochondrial toxicity may be involved.

              • The nucleoside/nucleotide reverse transcriptase inhibitors have various mitochondrial fax including inhibition of mitochondrial DNA polymerase-γ, a reduction in mitochondrial DNA/RNA levels as well as reduced mitochondrial function.

                • These mitochondrial effects may be sufficient to explain hyperlactataemia as well as many other abnormalities such as peripheral/autonomic neuropathy, skeletal/cardiomyopathy, steatohepatitis, pancreatitis as well as lipoatrophy.¹⁶

            • Stavudine side effects such as lipoatrophy, lipodystrophy, peripheral neuropathy and less frequently lactic acidosis and hepatitis have been sufficient to reduce the use of stavudine unless an alternative is unavailable.¹⁷ 

              • Patients receiving stavudine may be prescribed as an alternative abacavir or tenofovir.

            • Acute pancreatitis is not a major side effect with stavudine; however, pancreatitis is more likely when stavudine is administered along with didanosine.^1,18

              • Pancreatitis is more commonly observed in patient receiving didanosine (ddI) and outcomes of ddI continued administration in the presence of pancreatitis tend to worsen.

              • Combination of didanosine and stavuding increases risk and severity of peripheral neuropathy and life-threatening pancreatitis. 

                • Accordingly, these agents should not be used together.^1,18

            • Stavudine and zidovudine also compete for intracellular, drug-activating phosphorylation and therefore should not be co-administered.¹

        • Therapeutics:¹

          • Compared to zidovudine, stavudine delayed HIV disease progression and reduced plasma HIV RNA by 70%-90%.¹ 

            • The long-term virologic stavudine response was enhanced by lamivudine coadministration.

            • Significant and long-lasting viremia suppression along with sustained CD4 ⁺ T cell count elevation have been confirmed when stavudine is combined with other nucleoside analogues plus nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors.

            • As noted earlier, stavudine, as a consequence of toxicities, is used much less frequently in the developed world.

              • However, in "resource-poor" settings due to availability of relatively inexpensive generic forms and co-formulated with nevirapine and lamivudine, stavudine continues to be widely administered.¹

          • Examples of stavudine (Zerit) formulations