Rescriptor (Delavirdine Mesylate) Drug Information: Clinical Pharmacology

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May 27, 2012

Rescriptor

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CLINICAL PHARMACOLOGY

Microbiology

Mechanism of Action: Delavirdine is a non-nucleoside reverse transcriptase inhibitor(NNRTI) of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocksRNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template: primer or deoxy nucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1group 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-VHIV-1 activity of delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral bloodly mphocytes 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 to0.030 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 M. 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 (delavirdine mesylate) as monotherapy showed a 50- fold 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 (delavirdine mesylate) plus zidovudine combination therapy (N=79) showed resistance conferring mutations in all isolates by week 24 of therapy. In RESCRIPTOR (delavirdine mesylate) -treated patients 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 24weeks of RESCRI PTOR and zidovudine combination therapy. The clinical relevance of the phenotypic and the genotypic changes associated with RESCRIPTOR (delavirdine mesylate) therapy has not been established.

Cross-resistance: RESCRIPTOR (delavirdine mesylate) may confer cross-resistance to other non-nucleoside RT inhibitors when used alone or in combination. Mutations at positions 103 and/or 181 have been found in resistant virus during treatment with RESCRIPTOR (delavirdine mesylate) and other non-nucleoside RT inhibitors. These mutations have been associated with cross-resistance among non-nucleoside RT inhibitors in vitro.

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 stead y-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 ± 10µM (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 through out the study; meal content was not standardized. When multiple doses of delavirdine were administered with food, geometric mean Cmax wasreduced 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.

Co administered Drug	Dose of Coadministered Drug	Dose of RESCRIPTOR	n	% Change in Pharmacokinetic Parameters of Co administered Drug (90% CI)
Co administered Drug	Dose of Coadministered Drug	Dose of RESCRIPTOR	n	Cmax	AUC	Cmin
HIV-Protease Inhibitors
Indinavir	400 mg tid x 7 days	400 mg tid x 7 days	28	↓36* (↓52- ↓14)	↔*	↑118* (↑16- ↑312)
	600 mg tid x 7 days	400 mg tid x 7 days	28	↔	↑53* (↑7- ↑120)	↑298* (↑104- ↑678)
Nelfinavir^†	750 mg tid x 14 days	400 mg tid x7 days	12	↑88 (↑66- ↑113)	↑107 (↑83- ↑135)	↑136 (↑103- ↑175)
Saquinavir	Soft gel capsule 1000 mg tid x 28 days	400 mg tid x 28 days	20	↑98 ^‡ (↑4- ↑277)	↑121 ^‡(↑14- ↑340)	↑199^‡(↑37- ↑553)
*Nucleoside Reverse Transcriptase Inhibitors*
Didanosine (buffered tablets)	125 or 250 mg bid x 28 days	400 mg tid x 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 x 15 days	300 mg tid x 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)
↑Indicates increase ↓Indicates decrease ↔Indicates no significant change * Relative to indinavir 800 mg tid without RESCRIPTOR (delavirdine mesylate) ^†Plasma concentrations of the nelfinavir active metabolite (nelfinavir hydroxy-t-butylamide) were significantlyreduced by delavirdine, which is more than compensated for by increased nelfinavir concentration ^‡Saquinavir soft gel capsule 1000 mg tid plus RESCRIPTOR (delavirdine mesylate) 400 mg tid relative to saquinavir soft gel capsule1200 mg tid without RESCRIPTOR (delavirdine mesylate) ^§ RESCRIPTOR (delavirdine mesylate) taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR (delavirdine mesylate) and didanosine(buffered tablets) separated by at least 1 hr - Indicates no data available

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)
Coadministered Drug	Dose of Coadministered Drug	Dose of RESCRIPTOR	n	Cmax	AUC	Cmin
*HIV-Protease Inhibitors*
Indinavir	400 or 600 mg tid x 7 days	400 mg tid x 7 days	81	No apparent changes based on a comparison to historical data
Nelfinavir	750 mg tid x 7 days	400mg tid x 14 days	7	↓27 (↓49- ↑4)	↓31 (↓57- ↑10)	↓33 (↓70- ↑49)
Saquinavir	Soft gel capsule 1000 mg tid x 28 days	400 mg tid for 7-28 days	23	No a pparent changes based on a comparison to historical data
Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets)	125 or 200 mg bid x 28 days	400 mg tid x 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 x15 days	300 mg tid x30 days	6	↔	↔	↔
Fluconazole	400 mg qd x15 days	300 mg tid x 30 days	8	↔	↔	↔
Ketoconazole	Various	200-400 mg tid	26	-	-	50^†
Rifabutin	300 mg qd x 14 days	400 mg tid x 28 days	7	↓72 (↓61- ↓80)	↓82 (↓74- ↓88)	↓94 (↓90- ↓96)
Rifampin	600 mg qd x 15 days	400 mg tid x 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^†
↑Indicates increase ↓Indicates decrease ↔Indicates no significant change * RESCRIPTOR (delavirdine mesylate) taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR (delavirdine mesylate) and didanosine(buffered tablets) separated by at least 1 hr ^†Population pharmacokinetic data from efficacy studies - Indicates no data available

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-treatanalysis 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 studiesproduced 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 (delavirdine mesylate) (DLV; 400 mg tid), zidovudine (ZDV; 200 mg tid), and lamivudine (3TC; 150 mg bid) versus RESCRIPTOR (delavirdine mesylate) (400 mg tid) andzidovudine (200 mg tid) versus zidovudine (200 mg tid) and lamivudine (150 mg bid) in 373 HIV-1- Vinfected 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 111cells/mL for RESCRIPTOR (delavirdine mesylate) + ZDV + 3TC, 27 cells/mL for RESCRIPTOR (delavirdine mesylate) + ZDV, and 74 cells/mL for ZDV + 3TC.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIVRNA 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 RNA Below 400 copies/mL
Standard PCR Assay Protocol 21 Part 2
Intent-to-Treat Analysis

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

Table 3: Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part 2

Outcome	ZD V + 3TC (N = 124) %	DLV + ZDV (N = 125) %	DLV + ZDV + 3TC (N = 124)%
HI V RNA <400 cop ies/mL *	14	2	45
HI V RNA ≥ 400 copies/mL^†,^‡	64	52	31
Discontinued due to adverse events^‡	8	13	10
Discontinued due to other reasons^‡,^§	14	33	14
*Corresponds to rates at Week 52 in proportion curve ^†Virologic failures at or before Week 52 ^‡Considered to be treatment failure in the analysis ^§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 (delavirdine mesylate) (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- Vinfected 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 (delavirdine mesylate) + ZDV + ddI or ddC or 3TC and 56 cells/mL for ZDV + ddIor 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.

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

Percentage of Patients with HIV RNA Below 400 copies/mL Standard PCR Assay Protocol 13C Intent-to-Treat Analysis - Illustration

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

Outcome	ZDV + ddx^† (N = 173) %	ZDV + ddx + DLV (N = 172) %
HIV RNA <400 copies/mL *	10	29
HIV RNA ≥ 400 copies/mL ^§,‡	69	42
Discontinued due to adverse events ^§	7	12
Discontinued due to other reasons ^§\|\|	14	17
*Corresponds to rates at Week 54 in proportion curve ^†ddx = ddI or ddC or 3TC ^‡Virologic failures at or before Week 54 ^§Considered to be treatment failure in the analysis ^\|\|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 (delavirdine mesylate) 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 humanexposure to RESCRIPTOR (delavirdine mesylate) (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: 11/25/2008
This monograph has been modified to include the generic and brand name in many instances.