Zerit (Stavudine) - Description and Clinical Pharmacology

(Patient Information Leaflet Included)

DESCRIPTION

ZERIT^® is the brand name for stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV).

ZERIT (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, and magnesium stearate. The hard gelatin shell consists of gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and iron oxides. The capsules are printed with edible inks.

ZERIT (stavudine) for Oral Solution is supplied as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL stavudine solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

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

Stavudine is a white to off-white crystalline solid with the molecular formula C₁₀H₁₂N₂O₄ 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 (K_i=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 in vitro 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% (IC₅₀) ranged from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. In vitro, 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 in vitro 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 vitro (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 IC₅₀ 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 vitro.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Tables 1-3). Peak plasma concentrations (C_max) 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 in HIV-infected adults are shown in Table 1.

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

Parameter	ZERIT 40 mg BID Mean ± SD (n=8)
a from 0 to 24 hours.
AUC = area under the curve over 24 hours.
Cmax = maximum plasma concentration.
Cmin = trough or minimum plasma concentration.
AUC (ng•h/mL)a	2568 ± 454
Cmax (ng/mL)	536 ± 146
Cmin (ng/mL)	8 ± 9

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 2.

Metabolism

The metabolism of stavudine has not been elucidated in humans.

Elimination

In humans, renal elimination 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. The remaining 60% of the drug is presumably eliminated by endogenous pathways.

Table 2: Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults: Bioavailability, Distribution, and Clearance

Parameter	Mean ± SD	n
a following 1-hour IV infusion.
b following single oral dose.
c assuming a body weight of 70 kg.
d over 12-24 hours.
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

Special Populations

Pediatric

For pharmacokinetic properties of stavudine in pediatric patients see Table 3.

Table 3: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-Exposed or -Infected Pediatric Patients

Parameter	Ages 5 weeks to 15 years	n	Ages 14 to 28 days	n	Day of Birth	n
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.
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)c	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

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 4). C_max and T_max 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 4: Mean ± SD Pharmacokinetic Parameter Values of ZERIT^a in Adults with Varying Degrees of Renal Function

	Creatinine Clearance			Hemodialysis Patientsb n=11
	>50 mL/min n=10	26-50 mL/min n=5	9-25 mL/min n=5
a Single 40-mg oral dose.
b Determined while patients were off dialysis.
T½ = terminal elimination half-life.
NA = not applicable.
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 (mL/min)	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

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 PRECAUTIONS: Geriatric Use.)

Gender

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

Drug Interactions (see PRECAUTIONS: Drug Interactions)

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).

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 5 and 6 summarize the effects on AUC and C_max, 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 5: Results of Drug Interaction Studies with ZERIT: Effects of Coadministered Drug on Stavudine Plasma AUC and C_max Values

Drug	Stavudine Dosage	na	AUC of Stavudine (95% CI)	Cmax of Stavudine (95% CI)
↑ indicates increase.
↔ indicates no change, or mean increase or decrease of <10%..
a HIV-infected patients.
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	↔	↔

Table 6: Results of Drug Interaction Studies with ZERIT: Effects of Stavudine on Coadministered Drug Plasma AUC and C_max Values

Drug	Stavudine Dosage	na	AUC of Coadministered Drug (95% CI)	Cmax of Coadministered Drug (95% CI)
↔ indicates no change, or mean increase or decrease of <10%.
a HIV-infected patients.
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	↔	↔