A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rescriptor Pharmacology, Pharmacokinetics, Studies, Metabolism - Delavirdine mesylate
Rescriptor Pharmacology, Pharmacokinetics, Studies, Metabolism - Delavirdine mesylate
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 mM (range 2
to 100 mM), systemic exposure (AUC) was 180
± 100 mM • hr (range 5 to 515 mM
• hr) and trough concentration (Cmin) was 15 ± 10 mM
(range 0.1 to 45 mM). 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. Following
single-dose administration of delavirdine tablets with a high-fat meal (874
kcal, 57 g fat), mean Cmax was decreased by 60% and mean AUC was
decreased by 26%, relative to fasted administration (n=12, non-HIV–infected
subjects). In a multiple-dose 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, mean Cmax was reduced by 22% 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 mM. 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 apparent 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 and CYP2C19 activity. Inhibition of CYP3A 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
studied in patients <16 years or >65 years of age.
Gender: Following administration of delavirdine (400
mg every eight hours), median delavirdine AUC was 31% higher in female patients
(n=12) than in male patients (n=55).
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)
Antacids: In a single-dose study in twelve healthy volunteers,
simultaneous administration of 300 mg delavirdine with alumina and magnesia
oral suspension resulted in a 41 ± 19% reduction in delavirdine AUC (see PRECAUTIONS-Drug
Interactions).
Clarithromycin: In a study in six HIV-1–infected patients,
coadministration of clarithromycin (500 mg bid) with delavirdine (300 mg tid)
resulted in a 44 ± 50% increase in delavirdine AUC. Compared to historical data,
clarithromycin AUC was increased by approximately 100% and 14-hydroxyclarithromycin
AUC was decreased by 75%.
Didanosine: In a study in nine HIV-1–infected patients,
simultaneous administration of didanosine (125 mg or 250 mg bid) with delavirdine
(400 mg tid) for two weeks resulted in an approximately 20% decrease in both
didanosine AUC and delavirdine AUC, relative to when administration of delavirdine
and didanosine was separated by at least one hour (see PRECAUTIONS-Drug
Interactions).
Fluconazole: In a study in eight HIV-1–infected patients,
coadministration of fluconazole (400 mg once daily) with delavirdine (300 mg
tid) did not significantly alter the pharmacokinetics of delavirdine. Compared
to historical data, fluconazole pharmacokinetics were not altered by delavirdine.
Fluoxetine: Population pharmacokinetic data available
for 36 patients suggest that fluoxetine increases trough plasma delavirdine
concentrations by about 50%.
Indinavir: Preliminary data (n=14) indicate that delavirdine
inhibits the metabolism of indinavir such that coadministration of a 400 mg
single dose of indinavir with delavirdine (400 mg tid) resulted in indinavir
AUC values slightly less than those observed following administration of an
800 mg dose of indinavir alone. Also, coadministration of a 600 mg dose of indinavir
with delavirdine (400 mg tid) resulted in indinavir AUC values approximately
40% greater than those observed following administration of an 800 mg dose of
indinavir alone. Indinavir had no effect on delavirdine pharmacokinetics (see
PRECAUTIONS-Drug Interactions).
Ketoconazole: Population pharmacokinetic data available
for 26 patients suggest that ketoconazole increases trough plasma delavirdine
concentrations by about 50%.
Phenytoin, Phenobarbital, and Carbamazepine: Population
pharmacokinetic data available for eight patients suggest that coadministration
of phenytoin, phenobarbital, or carbamazepine with delavirdine results in a
substantial reduction in trough plasma delavirdine concentrations (see PRECAUTIONS-Drug
Interactions).
Rifabutin: In a study in seven HIV-1–infected patients,
coadministration of rifabutin (300 mg once daily) with delavirdine (400 mg tid)
resulted in an 80 ± 10% decrease in delavirdine AUC. Compared to historical
data, rifabutin AUC was increased by at least 100% (see PRECAUTIONS-Drug
Interactions).
Rifampin: In a study in seven HIV-1–infected patients,
coadministration of rifampin (600 mg once daily) with delavirdine (400 mg tid)
resulted in a 96 ± 4% decrease in delavirdine AUC (see PRECAUTIONS-Drug
Interactions).
Ritonavir: Preliminary data (n=13) indicate that coadministration
of delavirdine (400 mg or 600 mg bid) with ritonavir (300 mg bid) did not alter
ritonavir pharmacokinetics. Coadministration of ritonavir (300 mg bid) with
delavirdine (400 mg bid) did not significantly alter delavirdine pharmacokinetics
(n=9). The pharmacokinetic interaction between delavirdine and ritonavir at
their recommended doses has not been studied (see PRECAUTIONS-Drug
Interactions).
Saquinavir: In 13 healthy volunteers, coadministration
of saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a five-fold
increase in saquinavir AUC. In seven healthy volunteers, coadministration of
saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a 15 ± 16%
decrease in delavirdine AUC (see PRECAUTIONS-Drug
Interactions).
Sulfamethoxazole and Trimethoprim/Sulfamethoxazole (TMP/SMX):
Population pharmacokinetic data available for 311 patients suggest that the
pharmacokinetics of delavirdine are not affected by sulfamethoxazole or TMP/SMX.
Zidovudine: Zidovudine and delavirdine do not alter
one another’s pharmacokinetics.
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