Maraviroc (Page 5 of 10)

8.7 Hepatic Impairment

Maraviroc is principally metabolized by the liver; therefore, when administering this drug to patients with hepatic impairment, maraviroc concentrations may be increased. Maraviroc concentrations are higher when maraviroc 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive maraviroc 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. Maraviroc has not been studied in subjects with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment [ see Warnings and Precautions ( 5.1), Clinical Pharmacology ( 12.3) ].

10 OVERDOSAGE

The highest single dose administered in clinical trials was 1,200 mg. The dose-limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for maraviroc in patients receiving a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism.

Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300-mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc, or in a specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval [ see Clinical Pharmacology ( 12.2) ].

There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure, and ECG.
Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Hemodialysis had a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD [ see Clinical Pharmacology ( 12.3) ].

11 DESCRIPTION

Maraviroc is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

Maraviroc is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate. The tablets are coated with, Opadry II White contains lecithin, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
Maraviroc is chemically described as 4,4-Difluoro-N-[(1S)-3-[(3-exo)-3-[3-methyl-5- (1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]-cyclohexane carboxamide. The molecular formula is C ₂₉ H ₄₁ F ₂ N ₅ O and the structural formula is:

Maraviroc is a white to pale colored powder with a molecular weight of 513.67. It is freely soluble in methanol and hygroscopic.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Maraviroc is an HIV-1 antiviral drug [ see Microbiology ( 12.4) ].

12.2 Pharmacodynamics

Exposure-Response Relationship in Treatment-Experienced Adult Subjects

The relationship between maraviroc, modeled plasma trough concentration (C _min ) (1 to 9 samples per subject taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in Trials A4001027 and A4001028. The C _min , baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load less than 400 copies per mL at 24 weeks). Table 9 illustrates the proportions of subjects with virologic success (%) within each C _min quartile for 150-mg twice-daily and 300-mg twice-daily groups.

Table 9. Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1 to Q4)

	150 mg Twice Daily (with CYP3A Inhibitors)			300 mg Twice Daily (without CYP3A Inhibitors)
	n	Median C min	% Subjects with Virologic Success	n	Median C min	% Subjects with Virologic Success
Placebo	160	–	30.6	35	–	28.6
Q1	78	33	52.6	22	13	50.0
Q2	77	87	63.6	22	29	68.2
Q3	78	166	78.2	22	46	63.6
Q4	78	279	74.4	22	97	68.2

Exposure-Response Relationship in Treatment-Naive Adult Subjects
The relationship between maraviroc, modeled plasma trough concentration (C _min ) (1 to 12 samples per subject taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with lamivudine/zidovudine in Trial A4001026. Table 10 illustrates the proportion (%) of subjects with virologic success less than 50 copies per mL at 48 weeks within each C _min quartile for the 300-mg twice-daily dose. Table 10. Treatment-Naive Subjects with Virologic Success by C _min Quartile (Q1 to Q4)

	300 mg Twice Daily
	n	Median C min	% Subjects with Virologic Success
Q1	75	23	57.3
Q2	72	39	72.2
Q3	73	56	74.0
Q4	74	81	83.8

Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus 1 of 73 and 1 of 74 in Q3 and Q4, respectively.

Effects on Electrocardiogram

A placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 3 single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300, and 900 mg of maraviroc were -2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of greater than or equal to 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.