RESCRIPTOR

RESCRIPTOR- delavirdine mesylate tablet
KAISER FOUNDATION HOSPITALS

DESCRIPTION

RESCRIPTOR Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1-[3-[(1-methyl-ethyl)amino]-2- pyridinyl]-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is C22 H28 N6 O3 S•CH4 O3 S, and its molecular weight is 552.68. The structural formula is:

rescriptor structural formula
(click image for full-size original)

Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23°C is 2,942 mcg/mL at pH 1.0, 295 mcg/mL at pH 2.0, and 0.81 mcg/mL at pH 7.4.

Each RESCRIPTOR Tablet, for oral administration, contains 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of carnauba wax, colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, and microcrystalline cellulose. In addition, the 200-mg tablet contains hypromellose, Opadry White YS-1-18202-A, and Pharmaceutical Ink Black.

MICROBIOLOGY

Mechanism of Action

Delavirdine is an NNRTI of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template:primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine.

In Vitro HIV-1 Susceptibility: In vitro anti-HIV-1 activity of delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV-1. IC50 and IC90 values (50% and 90% inhibitory concentrations) for laboratory isolates (n = 5) ranged from 0.005 to 0.030 μM and 0.04 to 0.10 μM, respectively. Mean IC50 of clinical isolates (n = 74) was 0.038 μM (range: 0.001 to 0.69 μM); 73 of 74 clinical isolates had an IC50 ≤0.18 μM. The IC90 of 24 of these clinical isolates ranged from 0.05 to 0.10 μM. In drug combination studies of delavirdine with zidovudine, didanosine, zalcitabine, lamivudine, interferon-α, and protease inhibitors, additive to synergistic anti–HIV-1 activity was observed in cell culture. The relationship between the in vitro susceptibility of HIV-1 RT inhibitors and the inhibition of HIV replication in humans has not been established.

Drug Resistance: Phenotypic analyses of isolates from patients treated with RESCRIPTOR as monotherapy showed a 50- to 500-fold reduced susceptibility in 14 of 15 patients by Week 8 of therapy. Genotypic analysis of HIV-1 isolates from patients receiving RESCRIPTOR plus zidovudine combination therapy (n = 79) showed resistance-conferring mutations in all isolates by Week 24 of therapy. In patients treated with RESCRIPTOR, the mutations in RT occurred predominantly at amino acid positions 103 and less frequently at positions 181 and 236. In a separate study, an average of 86-fold increase in the zidovudine susceptibility of patient isolates (n = 24) was observed after 24 weeks of combination therapy with RESCRIPTOR and zidovudine. The clinical relevance of the phenotypic and the genotypic changes associated with therapy with RESCRIPTOR has not been established.

Cross-Resistance: RESCRIPTOR may confer cross-resistance to other NNRTIs when used alone or in combination. Mutations at positions 103 and/or 181 have been found in resistant virus during treatment with RESCRIPTOR and other NNRTIs. These mutations have been associated with cross-resistance among NNRTIs in vitro.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption and Bioavailability: Delavirdine is rapidly absorbed following oral administration, with peak plasma concentrations occurring at approximately 1 hour. Following administration of delavirdine 400 mg 3 times daily (n = 67, HIV-1–infected patients), the mean ±SD steady-state peak plasma concentration (Cmax ) was 35 ± 20 μM (range: 2 to 100 μM), systemic exposure (AUC) was 180 ± 100 μM•hr (range: 5 to 515 μM•hr), and trough concentration (Cmin ) was 15 ± 10 μM (range: 0.1 to 45 μM). The single-dose bioavailability of delavirdine tablets relative to an oral solution was 85% ± 25% (n = 16, non-HIV–infected subjects). The single-dose bioavailability of delavirdine tablets (100-mg strength) was increased by approximately 20% when a slurry of drug was prepared by allowing delavirdine tablets to disintegrate in water before administration (n = 16, non-HIV–infected subjects). The bioavailability of the 200-mg strength delavirdine tablets has not been evaluated when administered as a slurry because they are not readily dispersed in water (see DOSAGE AND ADMINISTRATION).

Delavirdine may be administered with or without food. In a multiple-dose, crossover study, delavirdine was administered every 8 hours with food or every 8 hours, 1 hour before or 2 hours after a meal (n = 13, HIV-1–infected patients). Patients remained on their typical diet throughout the study; meal content was not standardized. When multiple doses of delavirdine were administered with food, geometric mean Cmax was reduced by approximately 25%, but AUC and Cmin were not altered.

Distribution: Delavirdine is extensively bound (approximately 98%) to plasma proteins, primarily albumin. The percentage of delavirdine that is protein-bound is constant over a delavirdine concentration range of 0.5 to 196 μM. In 5 HIV-1–infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% ± 0.07% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in saliva (n = 5, HIV-1–infected patients who received delavirdine 400 mg 3 times daily) and semen (n = 5 healthy volunteers who received delavirdine 300 mg 3 times daily) were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval.

Metabolism and Elimination: Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. In a study of 14 C-delavirdine in 6 healthy volunteers who received multiple doses of delavirdine tablets 300 mg 3 times daily, approximately 44% of the radiolabeled dose was recovered in feces, and approximately 51% of the dose was excreted in urine. Less than 5% of the dose was recovered unchanged in urine. The parent plasma half-life of delavirdine increases with dose; mean half-life following 400 mg 3 times daily is 5.8 hours, with a range of 2 to 11 hours.

In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity. Inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week after discontinuation of drug.

Special Populations

Hepatic or Renal Impairment: The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated (see PRECAUTIONS).

Age: The pharmacokinetics of delavirdine have not been adequately studied in patients aged <16 years or >65 years.

Gender: Data from population pharmacokinetics suggest that the plasma concentrations of delavirdine tend to be higher in females than in males. However, this difference is not considered to be clinically significant.

Race: No significant differences in the mean trough delavirdine concentrations were observed between different racial or ethnic groups.

Drug Interactions

(See also PRECAUTIONS: Drug Interactions.)

Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effects of delavirdine on the geometric mean AUC, Cmax , and Cmin of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, Cmax , and Cmin of delavirdine.

For information regarding clinical recommendations, see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.

Table 1. Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Delavirdine
Coadministered Drug Dose of Coadministered Drug Dose of RESCRIPTOR n % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
Cmax AUC Cmin
HIV-Protease Inhibitors
Indinavir

400 mg t.i.d.

400 mg t.i.d.

28

↓36a

a

↑118 a

600 mg t.i.d.

400 mg t.i.d.

28

↑53 a

↑298 a

Nelfinavirb

750 mg t.i.d.

400 mg t.i.d.

12

↑88

↑107

↑136

Saquinavir

Soft gel capsule 1,000 mg t.i.d.

400 mg t.i.d.

20

↑98c

↑121c

↑199c

Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets) 125 or 250 mg b.i.d. for 28 days

400 mg t.i.d.

9

↓20d

↓21d

-
Zidovudine

200 mg t.i.d.

100 mg q.i.d. to 400 mg t.i.d. for

34 -
Anti-infective Agents
Clarithromycin

500 mg b.i.d.

300 mg t.i.d.

6 - ↑100 -
Rifabutin 300 mg q.d. for 15 to 99 days 400 to 1,000 mg t.i.d. for 45 to 129 days 5

↑128

↑230

↑452

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no significant change.

a Relative to indinavir 800 mg t.i.d. without RESCRIPTOR.

b Plasma concentrations of the nelfinavir active metabolite (nelfinavir hydroxy-t-butylamide) were significantly reduced by delavirdine, which is more than compensated for by increased nelfinavir concentration.

c Saquinavir soft gel capsule 1,000 mg t.i.d. plus RESCRIPTOR 400 mg t.i.d. relative to saquinavir soft gel capsule 1,200 mg t.i.d. without RESCRIPTOR.

d RESCRIPTOR taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR and didanosine (buffered tablets) separated by at least 1 hour.

- Indicates no data available.

Table 2. Pharmacokinetic Parameters for Delavirdine in the Presence of Coadministered Drugs

Coadministered

Dose of

Dose of RESCRIPTOR n % Change in Delavirdine Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
HIV-Protease Inhibitors
Indinavir 400 or 600 mg t.i.d. for 7 days

400 mg t.i.d.

81 No apparent changes based on a comparison to historical data
Nelfinavir

750 mg t.i.d.

400 mg t.i.d.

7

↓27

↓31

↓33

Saquinavir

Soft gel capsule 1,000 mg t.i.d.

400 mg t.i.d.

23 No apparent changes based on a comparison to historical data
Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets) 125 or 200 mg b.i.d. for 28 days 400 mg t.i.d. for 28 days 9

↓32a

↓19 a

a
Zidovudine

200 mg t.i.d.

400 mg t.i.d.

42 No apparent changes based on a comparison to historical data
Anti-infective Agents
Clarithromycin

500 mg b.i.d.

300 mg t.i.d.

6
Fluconazole

400 mg q.d.

300 mg t.i.d.

8
Ketoconazole Various 200 to 400 mg t.i.d. 26 - - ↑50b
Rifabutin

300 mg q.d.

400 mg t.i.d.

7

↓72

↓82

↓94

Rifampin

600 mg q.d.

400 mg t.i.d.

7

↓90

↓97

↓100

Sulfamethoxazole or

Various 200 to 400 mg t.i.d. 311 - - b
Other

Antacid

® TC)
20 mL

300 mg

12

↓52

↓44

-
Fluoxetine Various 200 to 400 mg t.i.d. 36 - - ↑50b
Phenytoin, Phenobarbital, Carbamazepine Various 300 to 400 mg t.i.d. 8 - - ↓90b

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no significant change.

a RESCRIPTOR taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR and didanosine (buffered tablets) separated by at least 1 hour.

b Population pharmacokinetic data from efficacy studies.

- Indicates no data available.

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