Stavudine

STAVUDINE — stavudine capsule
Camber Pharmaceuticals, Inc.

Rx only

(Patient Information Leaflet Included)

WARNING

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING STAVUDINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF STAVUDINE AND DIDANOSINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF STAVUDINE AND DIDANOSINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY)

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WHEN STAVUDINE WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE, IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION (SEE WARNINGS)

DESCRIPTION

Stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV).

Stavudine Capsules are supplied for oral administration in strengths of 15, 20, 30, and 40 mg of stavudine. Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose anhydrous, and magnesium stearate. The hard gelatin shell consists of gelatin, sodium lauryl sulfate, titanium dioxide, and iron oxides.The capsules are printed with Black ink containing black iron oxide E172 dye.

The chemical name for stavudine is 2′,3′-didehydro-3′-deoxythymidine. Stavudine has the following structural formula:

im607

Stavudine is a white to off-white crystalline solid with the molecular formula C10 H12 N2 O4 and a molecular weight of 224.2. The solubility of stavudine at 23° C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23° C is 0.144.

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

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.

Drug 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 mutations T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated mutation 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 mutations associated with zidovudine resistance. HIV-1 isolates with one or more zidovudine-resistance-associated mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) exhibited reduced susceptibility to stavudine in cell culture.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Tables 1-3). 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. Steady-state pharmacokinetic parameters of stavudine in HIV-infected adults are shown in Table 1.

Table 1: Steady-State Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults
Parameter Stavudine 40 mg BID Mean ± SD (n=8)
AUC (ng•h/mL)a 2568 ± 454
Cmax (ng/mL) 536 ± 146
Cmin (ng/mL) 8 ± 9
a from 0 to 24 hoursAUC = 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 11.4µg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 2.

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 14 C-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 14 C-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-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 2). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Table 2: Pharmacokinetic Parameters of Stavudine in HIV-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.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.