Recommended Topic Related To:

Zerit

"A new analysis of data from 20 major U.S. cities reveals continued signs of sexual risk among gay and bisexual men, but shows dramatically lower sexual risk among those who accurately know their HIV status. The findings were published today in CD"...

Zerit

CLINICAL PHARMACOLOGY

Mechanism of Action

Stavudine is an antiviral drug.

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of ZERIT (stavudine) in HIV-1-infected adults are shown in Table 7.

Table 7: Steady-State Pharmacokinetic Parameters of ZERIT in HIV-1-Infected Adults

Parameter ZERIT 40 mg BID
Mean ± SD
(n=8)
AUC0–24 (ng•h/mL) 2568 ± 454
Cmax (ng/mL) 536 ± 146
Cmin (ng/mL) 8 ± 9
AUC0–24 = Area under the curve over 24 hours.
Cmax = Maximum plasma concentration.
Cmin = Trough or minimum plasma concentration.

Distribution

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 μg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80-mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.

Elimination

Following an 80-mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Table 8: Pharmacokinetic Parameters of Stavudine in HIV-1-Infected Adults: Bioavailability, Distribution, and Clearance

Parameter Mean ± SD n
Oral bioavailability (%) 86.4 ± 18.2 25
Volume of distribution (L)a 46 ± 21 44
Total body clearance (mL/min)a 594 ± 164 44
Apparent oral clearance (mL/min)b 560 ± 182c 113
Renal clearance (mL/min)a 237 ± 98 39
Elimination half-life, IV dose (h)a 1.15 ± 0.35 44
Elimination half-life, oral dose (h)b 1.6 ± 0.23 8
Urinary recovery of stavudine (% of dose) a,d 42 ± 14 39
a Following 1-hour IV infusion.
b Following single oral dose.
c Assuming a body weight of 70 kg.
d Over 12–24 hours.

Special Populations

Pediatric

Pharmacokinetic parameters of stavudine in pediatric patients are presented in Table 9.

Table 9: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-1-Exposed or -Infected Pediatric Patients

Parameter Ages 5 weeks to 15 years n Ages 14 to 28 days n Day of Birth n
Oral bioavailability (%) 76.9 ± 31.7 20 ND   ND  
Volume of distribution (L/kg)a 0.73 ± 0.32 21 ND   ND  
Ratio of CSF: plasma concentrations (as %)b 59 ± 35 8 ND   ND  
Total body clearance (mL/min/kg)a 9.75 ± 3.76 21 ND   ND  
Apparent oral clearance (mL/min/kg)c 13.75 ± 4.29 20 11.52 ± 5.93 30 5.08 ± 2.80 17
Elimination half-life, IV dose (h)a 1.11 ± 0.28 21 ND   ND  
Elimination half-life, oral dose (h)a 0.96 ± 0.26 20 1.59 ± 0.29 30 5.27 ± 2.01 17
Urinary recovery of stavudine (% of dose)c,d 34±16 19 ND   ND  
a Following 1-hour IV infusion.
b At median time of 2.5 hours (range 2–3 hours) following multiple oral doses.
c Following single oral dose.
d Over 8 hours. ND = Not determined.

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 10). Cmax and Tmax were not significantly altered by renal impairment. The mean ± SD hemodialysis clearance value of stavudine was 120 ± 18 mL/min (n=12); the mean ± SD percentage of the stavudine dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that ZERIT (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see DOSAGE AND ADMINISTRATION].

Table 10: Mean ± SD Pharmacokinetic Parameter Values of ZERITa in Adults with Varying Degrees of Renal Function

  Creatinine Clearance Hemodialysisb
> 50 mL/min (n=10) 26–50 mL/min (n=5) 9–25 mL/min (n=5) Patients (n=11)
Creatinine clearance (mL/min) 104 ± 28 41 ± 5 17 ± 3 NA
Apparent oral clearance (mL/min) 335 ± 57 191 ± 39 116 ± 25 105 ± 17
Renal clearance 167 ± 65 73 ± 18 17 ± 3 NA
T½ (h) 1.7 ± 0.4 3.5 ± 2.5 4.6 ± 0.9 5.4 ± 1.4
a Single 40-mg oral dose.
b Determined while patients were off dialysis.
T½= Terminal elimination half-life.
NA = Not applicable.

Hepatic Impairment

Stavudine pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40-mg dose.

Geriatric

Stavudine pharmacokinetics have not been studied in patients > 65 years of age. [See Use In Specific Populations.]

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males (n=291) and females (n=27).

Race

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other).

Drug Interaction Studies

Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs.

Tables 11 and 12 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI) when available, following coadministration of ZERIT with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Table 11: Results of Drug Interaction Studies with ZERIT: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values

Drug Stavudine Dosage na AUC of Stavudine
(95% CI)
Cmax of Stavudine
(95% CI)
Didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10 ↑17%
Lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (92.7–100.6%) ↑12% (100.3–126.1%)
Nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8
↑ Indicates increase.
↔ Indicates no change, or mean increase or decrease of < 10%.
a HIV-1-infected patients.

Table 12: Results of Drug Interaction Studies with ZERIT: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values

Drug Stavudine Dosage na AUC of Coadministered Drug (95% CI) Cmax of Coadministered Drug (95% CI)
Didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10
Lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (90.5–107.6%) ↔ (87.1–110.6%)
Nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8
↔ Indicates no change, or mean increase or decrease of < 10%.
a HIV-1-infected patients.

Microbiology

Mechanism of Action

Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=0.0083 to 0.032 μM) and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity in Cell Culture

The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50) ranged from 0.009 to 4 μM against laboratory and clinical isolates of HIV-1. In cell culture, stavudine exhibited additive to antagonistic activity in combination with zidovudine. Stavudine in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9–45 μM concentrations tested, reduced the anti-HIV-1 activity of stavudine by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been established.

Resistance

HIV-1 isolates with reduced susceptibility to stavudine have been selected in cell culture (strain-specific) and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6–29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited EC50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified.

Cross-resistance

Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged stavudine treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to stavudine in cell culture. These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutations.

Clinical Studies

Combination Therapy

The combination use of ZERIT is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing ZERIT (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+ cell counts through 48 weeks.

Monotherapy

The efficacy of ZERIT was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992–1994) comparing ZERIT with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

Last reviewed on RxList: 12/6/2011
This monograph has been modified to include the generic and brand name in many instances.

A A A

Zerit - User Reviews

Zerit User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Zerit sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


WebMD Daily

Get breaking medical news.


NIH talks about Ebola on WebMD