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. 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.
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Table 1 : Steady-State Pharmacokinetic Parameters of ZERIT in HIV-Infected Adults |
|
Parameter |
ZERIT 40 mg BID Mean ¡ÀSD (n=8) |
|
AUC (ng.h/mL)a |
2568 ¡À 454 |
|
Cmax (ng/mL) |
536 ¡À146 |
|
Cmin (ng/mL) |
8 ¡À9 |
|
afrom 0 to 24 hours |
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AUC = area under the curve over 24 hours. |
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Cmax = maximum plasma concentration. |
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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 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.
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Table 2 Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults: Bioavailability, Distribution, and Clearance |
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Parameter |
Mean ¡À SD |
n |
|
Oral bioavailability (%) |
86.4 ¡À18.2 |
25 |
|
Volume of distribution (L)a |
46 ¡À 21 |
44 |
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Total body clearance (mL/min)a |
594 ¡À 164 |
44 |
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Apparent oral clearance (mL/min)b |
560 ¡À 182c |
113 |
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Renal clearance (mL/min)a |
237 ¡À 98 |
39 |
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Elimination half-life, IV dose (h)a |
1.15 ¡À 0.35 |
44 |
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Elimination half-life, oral dose (h)b |
1.6 ¡À 0.23 |
8 |
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Urinary recovery of stavudine (% of dose)a,d |
42 ¡À 14 |
39 |
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a following 1-hour IV infusion. |
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b following single oral dose. |
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c assuming a body weight of 70 kg. |
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d over 12-24 hours. |
Special Populations
Pediatric- For pharmacokinetic properties of stavudine in pediatric patients, see Table 3.
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Table 3 Pharmacokinetic Parameters (Mean ¡ÀSD) of Stavudine in HIV-Exposed or -Infected Pediatric Patients |
|
Parameter |
Ages 5 weeks to 15 years |
n |
Ages 14to 28 days |
n |
Day of Birth |
|
| |
|
|
|
|
n |
|
|
Oral bioavailability (%) |
76.9 ¡À31.7 |
20 |
ND |
|
ND |
|
|
Volume of distributiona (L/kg) |
0.73 ¡À0.32 |
21 |
ND |
|
ND |
|
|
Ratio of CSF: plasma concentrations (as %)b |
59 ¡À 35 |
8 |
ND |
|
ND |
|
|
Total body clearancea (mL/min/kg) |
9.75 ¡À3.76 |
21 |
ND |
|
ND |
|
|
Apparent oral clearancec (mL/min/kg) |
13.75 ¡À 4.29 |
20 |
11.52 ¡À 5.93 |
30 |
5.08 ¡À 2.80 |
17 |
|
Elimination half-life,I.V. dosea (h) |
1.11 ¡À0.28 |
21 |
ND |
|
ND |
|
|
Elimination half-life,oral dosec (h) |
0.96 ¡À 0.26 |
20 |
1.59 ¡À 0.29 |
30 |
5.27 ¡À 2.01 |
17 |
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Urinary recovery of stavudine (% of dose)c,d |
34 ¡À 16 |
19 |
ND |
|
ND |
|
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a following 1 hour I.V. infusion. |
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b at median time of 2.5 hours (range 2-3 hours) following multiple oral doses. |
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c following single oral dose. |
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d over 8 hours. |
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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 4). Cmax and Tmax were not significantly altered by renal impairment. The mean ¡À SD hemodialysis clearance value of stavudine was 120 ¡À18 mL/min (n=12); the mean ¡ÀSD percentage of the stavudine dose recovered in the dialysate, timed to occur between 2-6 hours post-dose, was 31 ¡À5%. 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).
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Table 4 Mean ¡ÀSD Pharmacokinetic Parameter Values of ZERITa in Adults with Varying Degrees of Renal Function |
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Creatinine Clearance |
Hemodialysis Patientsb |
| |
>50 mL/min |
26-50 mL/min |
9-25 mL/min |
| |
(n=10) |
(n=5) |
(n=5) |
(n=11) |
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Creatinine clearance (mL/min) |
104 ¡À28 |
41 ¡À5 |
17 ¡À3 |
NA |
|
Apparent oral clearance (mL/min) |
335 ¡À57 |
191 ¡À 39 |
116 ¡À 25 |
105 ¡À 17 |
|
Renal clearance (mL/min) |
167 ¡À 65 |
73 ¡À 18 |
17 ¡À 3 |
NA |
|
T ½ (h) |
1.7 ¡À 0.4 |
3.5 ¡À 2.5 |
4.6 ¡À 0.9 |
5.4 ¡À 1.4 |
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a Single 40-mg oral dose. |
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b Determined while patients were off dialysis. |
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T ½ = terminal elimination half-life. |
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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 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 competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT (stavudine) should be avoided.
In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin and ribavirin.
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 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.
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Table 5 Results of Drug Interaction Studies with ZERIT: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values |
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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 |
« |
¡ü17% |
|
Lamivudine, 150 mg single dose |
40 mg single dose |
18 |
« (92.7-100.6%) |
¡ü12% (100.3-126.1%) |
|
Nelfinavir, 750 mg q8h for 56 days |
30-40 mg q12h for 56 days |
8 |
« |
« |
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¡ü indicates increase. |
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«indicates no change, or mean increase or decrease of <10%. |
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a HIV-infected patients. |
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Table 6 Results of Drug Interaction Studies with ZERIT: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values |
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Drug |
Stavudine Dosage |
na |
AUC of Coadministered Drug (95% CI) |
Cmax of Coadministere 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 |
« |
« |
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«indicates no change, or mean increase or decrease of <10%. |
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a HIV-infected patients. |
CLINICAL STUDIES
Combination Therapy- The combination use of ZERIT is based on the results of clinical studies in HIV-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 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-related symptoms. The outcome in terms of progression of HIV disease and death was similar for both drugs
