CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption and Bioavailability
Delavirdine is rapidly absorbed following oral administration, with peak plasma concentrations occurring at approximately one hour. Following administration of delavirdine 400 mg tid (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 eight hours with food or every eight hours, one hour before or two 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 five HIV-1–infected patients whose total daily dose of delavirdine ranged from 600 to 1200 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 tid) and semen (n=5 healthy volunteers who received delavirdine 300 mg tid) 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 1200 mg/day. In a study of 14C-delavirdine in six healthy volunteers who received multiple doses of delavirdine tablets 300 mg tid, 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 tid 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 <16 years or >65 years of age.
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 |
|---|
| ↑ Indicates increase |
| ↓ Indicates decrease |
| ↔ Indicates no significant change |
| - Indicates no data available |
| HIV-Protease Inhibitors |
| Indinavir | 400 mg tid × 7 days | 400 mg tid × 7 days | 28 | ↓36
(↓52–↓14) | ↔ | ↑118
(↑16–↑312) |
| 600 mg tid × 7 days | 400 mg tid × 7 days | 28 | ↔ | ↑53
(↑7–↑120) | ↑298
(↑104–↑678) |
| NelfinavirPlasma 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 | 750 mg tid × 14 days | 400 mg tid × 7 days | 12 | ↑88
(↑66–↑113) | ↑107
(↑83–↑135) | ↑136
(↑103–↑175) |
| Saquinavir | Soft gel capsule 1000 mg tid × 28 days | 400 mg tid × 28 days | 20 | ↑98
(↑4–↑277) | ↑121
(↑14–↑340) | ↑199
(↑37–↑553) |
| Nucleoside Reverse Transcriptase Inhibitors |
| Didanosine (buffered tablets) | 125 or 250 mg bid × 28 days | 400 mg tid × 28 days | 9 | ↓20
(↓44–↑15) | ↓21
(↓40–↑5) | - |
| Zidovudine | 200 mg tid for >38 days | 100 mg qid to 400 mg tid for 8–10 days | 34 | ↔ | ↔ | - |
| Anti-infective Agents |
| Clarithromycin | 500 mg bid × 15 days | 300 mg tid × 30 days | 6 | - | ↑100 | - |
| Rifabutin | 300 mg qd for 15–99 days | 400–1000 mg tid for 45–129 days | 5 | ↑128
(↑71–↑203) | ↑230
(↑119–↑396) | ↑452
(↑246–↑781) |
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 |
|---|
| ↑ Indicates increase |
| ↓ Indicates decrease |
| ↔ Indicates no significant change |
| - Indicates no data available |
| HIV-Protease Inhibitors |
| Indinavir | 400 or 600 mg tid × 7 days | 400 mg tid× 7 days | 81 | No apparent changes based on a comparison to historical data |
| Nelfinavir | 750 mg tid × 7 days | 400 mg tid × 14 days | 7 | ↓27
(↓49–↑4) | ↓31
(↓57–↑10) | ↓33
(↓70–↑49) |
| Saquinavir | Soft gel capsule 1000 mg tid × 28 days | 400 mg tid for 7–28 days | 23 | No apparent changes based on a comparison to historical data |
| Nucleoside Reverse Transcriptase Inhibitors |
| Didanosine (buffered tablets) | 125 or 200 mg bid × 28 days | 400 mg tid × 28 days | 9 | ↓32
(↓48–↓11) | ↓19
(↓37–↑6) | ↔ |
| Zidovudine | 200 mg tid for ≥ 7 days | 400 mg tid for 7–14 days | 42 | No apparent changes based on a comparison to historical data |
| Anti-infective Agents |
| Clarithromycin | 500 mg bid × 15 days | 300 mg tid × 30 days | 6 | ↔ | ↔ | ↔ |
| Fluconazole | 400 mg qd × 15 days | 300 mg tid × 30 days | 8 | ↔ | ↔ | ↔ |
| Ketoconazole | Various | 200–400 mg tid | 26 | - | - | ↑50
|
| Rifabutin | 300 mg qd × 14 days | 400 mg tid × 28 days | 7 | ↓72
(↓61–↓80) | ↓82
(↓74–↓88) | ↓94
(↓90–↓96) |
| Rifampin | 600 mg qd × 15 days | 400 mg tid × 30 days | 7 | ↓90
(↓94–↓83) | ↓97
(↓98–↓95) | ↓100 |
| Sulfamethoxazole or Trimethoprim & Sulfamethoxazole | Various | 200–400 mg tid | 311 | - | - | ↔ |
| Other |
| Antacid (Maalox® TC) | 20 mL | 300 mg single dose | 12 | ↓52
(↓68–↓29) | ↓44
(↓58–↓27) | - |
| Fluoxetine | Various | 200–400 mg tid | 36 | - | - | ↑50 |
| Phenytoin, Phenobarbital, Carbamazepine | Various | 300–400 mg tid | 8 | - | - | ↓90 |
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.
LAB-0059-5.0
June 2006
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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 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 < 400copies/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 (DLV; 400 mg tid), zidovudine (ZDV; 200 mg tid), and lamivudine (3TC; 150 mg bid) versus RESCRIPTOR (400 mg tid) and zidovudine (200 mg tid) versus zidovudine (200 mg tid) and lamivudine (150 mg bid) 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 RNA was 4.4 log10 copies/mL.
Results showed that the mean increase from baseline in CD4 count at 52 weeks was 111 cells/mL for RESCRIPTOR + ZDV + 3TC, 27 cells/mL for RESCRIPTOR + ZDV, and 74 cells/mL for ZDV + 3TC.
The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV 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.
Table 3: Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part 2 | Outcome | ZDV + 3TC
(N = 124)
% | DLV + ZDV
(N = 125)
% | DLV + ZDV + 3TC
(N = 124)
% |
|---|
| HIV RNA <400 copies/mLCorresponds to rates at Week 52 in proportion curve | 14 | 2 | 45 |
| HIV RNA ≥400 copies/mLVirologic failures at or before Week 52,
| 64 | 52 | 31 |
| Discontinued due to adverse events | 8 | 13 | 10 |
| Discontinued due to other reasons,Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons | 14 | 33 | 14 |
Study 13C
Study 13C was a double-blind, randomized, placebo-controlled trial comparing treatment with RESCRIPTOR (400 mg tid), zidovudine (200 mg tid or 300 bid) and either didanosine (ddI; 200 mg bid), zalcitabine (ddC; 0.75 mg tid) or lamivudine (150 mg bid) versus zidovudine (200 mg tid or 300 mg bid) and either didanosine (200 mg bid), zalcitabine (0.75 mg tid) or lamivudine (150 mg bid) 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 RNA was 4.9 log10 copies/mL.
Results showed that the mean increase from baseline in CD4 count at 54 weeks was 102 cells/mL for RESCRIPTOR + ZDV + ddI or ddC or 3TC and 56 cells/mL for ZDV + ddI or ddC or 3TC.
The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV 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.
Table 4. Outcomes of Randomized Treatment Through Week 54 for Protocol 13C | Outcome | ZDV + ddxddx = ddI or ddC or 3TC
(N = 173)
% | ZDV + ddx + DLV
(N = 172)
% |
|---|
| HIV RNA <400 copies/mLCorresponds to rates at Week 54 in proportion curve | 10 | 29 |
| HIV RNA ≥400 copies/mL
,Virologic failures at or before Week 54 | 69 | 42 |
| Discontinued due to adverse events | 7 | 12 |
| Discontinued due to other reasonsIncludes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons | 14 | 17 |
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.
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