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Rescriptor

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Rescriptor

CLINICAL PHARMACOLOGY

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 and 0.04 to 0.10 respectively. Mean IC50 of clinical isolates (n = 74) was 0.038 (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-a, 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.

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 515μM •hr), and trough concentration (Cmin) was 15 ± 10 (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 14C-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

Coadministeied 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. for 7 days 400 mg t.i.d. for 7 days 28 ↓36a
(↓52 to ↓14)
a ↑118 a
(↑ 16 to ↑312)
600 mg t.i.d. for 7 days 400 mg t.i.d. for 7 days 28 ↑53 a
(↑7 to ↑120)
↑298 a
(↑104 to ↑678)
Nelfinavirb 750 mg t.i.d. for 14 days 400 mg t.i.d. for 7 days 12 ↑88
(↑66 to ↑113)
↑107
(↑83 to ↑135)
↑136
(↑ 103 to ↑175)
Saquinavir Soft gel capsule 1,000 mg t.i.d. for 28 days 400 mg t.i.d. for 28 days 20 ↑98c (↑4 to ↑277) ↑121c (↑ 14 to ↑340) ↑199c
(↑37 to ↑553)
Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets) 125 or 250 mg b.i.d. for 28 days 400 mg t.i.d. for 28 days 9 ↓20d (↓44 to ↑15) ↓21d (↓40 to ↑5) -
Zidovudine 200 mg t.i.d. for >38 days 100 mg q.i.d. to 400 mg t.i.d. for 8 to 10 days 34 -
Anti-infective Agents
Clarithromycin 500 mg b.i.d. for 15 days 300 mg t.i.d. for 30 days 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
(↑71 to ↑203)
↑230
(↑119 to ↑396)
↑452
(↑246 to ↑781)
↑Indicates increase.
↓Indicates decrease.
↔Indicates no significant change.
-Indicates no data available.
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.

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

Coadministered Drug Dose of Coadministered Drug 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. for 7 days 81 No apparent changes based on a comparison to historical data
Nelfinavir 750 mg t.i.d. for 7 days 400 mg t.i.d. for 14 days 7 ↓27
(↓49 to ↑4)
↓31
(↓57 to ↑10)
↓33
(↓70 to ↑49)
Saquinavir Soft gel capsule 1,000 mg t.i.d. for 28 days 400 mg t.i.d. for 7 to 28 days 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
(↓48 to↓11)
↓19a
(↓37 to ↑6)
a
Zidovudine 200 mg t.i.d. for >7 days 400 mg t.i.d. for 7 to 14 days 42 No apparent changes based on a comparison to historical data
Anti-infective Agents
Clarithromycin 500 mg b.i.d. for 15 days 300 mg t.i.d. for 30 days 6
Fluconazole 400 mg q.d. for 15 days 300 mg t.i.d. for 30 days 8
Ketoconazole Various 200 to 400 mg t.i.d. 26 - - ↑50b
Rifabutin 300 mg q.d. for 14 days 400 mg t.i.d. for 28 days 7 ↓72
(↓61 to ↓80)
↓82
(↓74 to ↓88)
↓94
(↓90 to ↓96)
Rifampin 600 mg q.d. for 15 days 400 mg t.i.d. for 30 days 7 ↓90
(↓94 to ↓83)
↓97
(↓98 to ↓95)
↓100
Sulfamethoxazole or Trimethoprim & Sulfamethoxazole Various t.i.d. 200 to 400 mg 311 - - b
Other
Antacid (Maalox® TC) 20 mL 300 mg single dose 12 ↓52
(↓68 to ↓29)
↓44
(↓58 to ↓27)
-
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.
-Indicates no data available.
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.

Description Of Clinical Studies

For clinical Studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV-1 RNA level < 400 copies/mL through Week 52 as measured by the Roche Amplicor® HIV-1 Monitor (standard assay). An intent-to-treat analysis was performed where only subjects who achieved confirmed suppression and sustained it through Week 52 are regarded as responders. All other subjects (including never suppressed, discontinued, and those who rebounded after initial suppression of < 400 copies/mL) are considered failures at Week 52. Results of an interim analysis of efficacy conducted for studies 21 Part II and 13C by independent Data and Safety Monitoring Boards (DSMBs) revealed that the triple-therapy arms in both studies produced significantly greater antiviral benefit than the dual-therapy arms, and early termination of the studies was recommended.

Study 21 Part II

Study 21 Part II was a double-blind, randomized, placebo-controlled trial comparing treatment with RESCRIPTOR (400 mg 3 times daily, zidovudine 200 mg 3 times daily, and lamivudine 150 mg twice daily versus RESCRIPTOR 400 mg 3 times daily and zidovudine 200 mg 3 times daily versus zidovudine 200 mg 3 times daily and lamivudine 150 mg twice daily in 373 HIV-1-infected patients (mean age 35 years [range: 17 to 67], 87% male, and 60% Caucasian) who were antiretroviral treatment naive (84%) or had limited nucleoside experience (16%). Mean baseline CD4+ cell count was 359 cells/mm³ and mean baseline plasma HIV-1 RNA was 4.4 log10 copies/mL.

Results showed that the mean increases from baseline in CD4 cell counts at 52 weeks were 111 cells/mL for RESCRIPTOR + zidovudine + lamivudine, 27 cells/mL for RESCRIPTOR + zidovudine, and 74 cells/mL for zidovudine + lamivudine.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level < 400 copies/mL are presented in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 3. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 1: Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 21 Part II: Intent-to-Treat Analysis

Percentage of Patients With HIV-1 RNA Below 400 copies/mL Illustration

Table 3: Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part II

Outcome Zidovudine + Lamivudine
(n = 124) %
RESCRIPTOR + Zidovudine
(n = 125) %
RESCRIPTOR + Zidovudine + Lamivudine
(n = 124) %
HIV-1 RNA < 400 copies/mLa 14 2 45
HIV-1 RNA ≥ 400 copies/mLb,c 64 52 31
Discontinued due to adverse eventsc 8 13 10
Discontinued due to other reasonsc,d 14 33 14
a Corresponds to rates at Week 52 in proportion curve.
b Virologic failures at or before Week 52.
c Considered to be treatment failure in the analysis.
d Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Study 13C

Study 13C was a double-blind, randomized, placebo-controlled trial comparing treatment with RESCRIPTOR 400 mg 3 times daily, zidovudine 200 mg 3 times daily or 300 mg twice daily, and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily versus zidovudine 200 mg 3 times daily or 300 mg twice daily and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily in 345 HIV-1-infected patients (mean age 35.8 years [range: 18 to 72], 66% male, and 63% Caucasian) who were antiretroviral treatment naive (63%) or had limited antiretroviral experience (37%). Mean baseline CD4+ cell count was 210 cells/mm³ and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL.

Results showed that the mean increases from baseline in CD4+ cell counts at 54 weeks were 102 cells/mL for RESCRIPTOR + zidovudine + didanosine or zalcitabine or lamivudine, and 56 cells/mL for zidovudine + didanosine or zalcitabine or lamivudine.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level < 400 copies/mL are presented in Figure 2. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 4. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 2: Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 13C: Intent-to-Treat Analysis

Percentage of Patients With HIV-1 RNA Below 400 copies/mL - Illustration

Table 4: Outcomes of Randomized Treatment Through Week 54 for Protocol 13C

Outcome Zidovudine + Didanosine or Zalcitabine or Lamivudine
(n =173) %
Zidovudine + Didanosine or Zalcitabine or Lamivudine + RESCRIPTOR
(n = 172) %
HIV-1 RNA < 400 copies/mLa 10 29
HIV-1 RNA ≥ 400 copies/mLb,c 69 42
Discontinued due to adverse eventsc 7 12
Discontinued due to other reasonsc,d 14 17
a Corresponds to rates at Week 54 in proportion curve.
b Virologic failures at or before Week 54.
c Considered to be treatment failure in the analysis.
d Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Results from several smaller supportive studies evaluating the use of RESCRIPTOR in treatment-naive patients suggest that it may have activity when used in combination with protease inhibitors and NRTIs in 3- or 4-drug combinations.

Animal Toxicology

Toxicities among various organs and organ systems in rats, mice, rabbits, dogs, and monkeys were observed following the administration of delavirdine. Necrotizing vasculitis was the most significant toxicity that occurred in dogs when mean nadir serum concentrations of delavirdine were at least 7-fold higher than the expected human exposure to RESCRIPTOR (Cmin 15 μM) at the recommended dose. Vasculitis in dogs was not reversible during a 2.5-month recovery period; however, partial resolution of the vascular lesion characterized by reduced inflammation, diminished necrosis, and intimal thickening occurred during this period. Other major target organs included the gastrointestinal tract, endocrine organs, liver, kidneys, bone marrow, lymphoid tissue, lung, and reproductive organs.

Last reviewed on RxList: 8/29/2012
This monograph has been modified to include the generic and brand name in many instances.

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