Lofexidine

Lofexidine is a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.

Cardiac Electrophysiology

Single lofexidine doses of 1.44 to 1.8 mg produced maximum mean change from baseline in QTcF (ΔQTcF) of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec) for 1.44 and 1.8 mg respectively in healthy normal volunteers.

In a Phase 3 placebo-controlled, dose response study in opioid dependent subjects, lofexidine was associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8) and 9.3 (10.9) msec at doses of 2.16 and 2.88 mg/day, respectively.

Patients with hepatic impairment

Administration of lofexidine to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment.

Patients with renal impairment

Administration of lofexidine to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment.

Lofexidine coadministered with methadone

Lofexidine (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80-120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec.

Lofexidine coadministered with buprenorphine

Lofexidine (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16-24 mg/day) resulted in a maximum mean QTcF increase in QTcF of 15 (5.6) msec compared to a buprenorphine-alone baseline.

In Vitro Binding

Lofexidine exhibits in vitro binding affinity and functional agonist activity with alpha-2A and alpha-2C adrenoreceptors at concentrations within clinical exposure plasma levels (Ki values of approximately 7.2 nM and 12 nM, and EC₅₀ values of 4.9 nM and 0.9 nM, respectively).

Absorption

Lofexidine is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose.

Lofexidine shows approximately dose-proportional pharmacokinetics. Administration of lofexidine with food does not alter its pharmacokinetics.

The absolute bioavailability of a single oral lofexidine dose (0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean lofexidine C_max after the oral dose and intravenous infusion was 0.82 ng/mL (at median T_max of 3 hours) and 0.64 ng/mL (at median T_max of 4 hours), respectively. Mean estimates of overall systemic exposure (AUC_inf) were 14.9 ng∙h/mL and 12.0 ng∙h/mL, respectively.

Distribution

Mean lofexidine apparent volume of distribution and volume of distribution values following the administration of an oral dose and an intravenous dose were 480.0 L and 297.9 L, respectively, which are appreciably greater than total body volume, suggesting extensive lofexidine distribution into body tissue.

Lofexidine protein binding is approximately 55%.

Lofexidine is not preferentially taken up by blood cells. In a study comparing lofexidine concentrations in plasma and whole blood at the time of peak lofexidine concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the lofexidine concentration of the plasma.

Elimination

Metabolism

From absolute bioavailability results, approximately 30% of the administered lofexidine dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut.

Lofexidine and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by lofexidine, with an IC₅₀ of 4551 nM (approximately 225 times the steady-state C_max for lofexidine with 0.72 mg 4 times daily dosing). Any lofexidine interaction with CYP2D6 substrates is not expected to be clinically significant.

Lofexidine is metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of lofexidine is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine.

Excretion

The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion.

Lofexidine has a terminal half-life of approximately 11 to 13 hours following the first dose. At steady-state, the terminal half-life is approximately 17 to 22 hours. Accumulation occurs up to 4 days with repeat dosing, following the recommended dosing regimen.

A mass balance study of lofexidine showed nearly complete recovery of radiolabel in urine (93.5%) over 144 hours postdose, with an additional 0.92% recovered in the feces over 216 hours postdose. Thus, it appears that all, or nearly all, of the dose was absorbed, and that the primary route of elimination of the parent drug and its metabolites is via the kidney. Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose.

Specific Populations

Hepatic Impairment

Hepatic impairment slows the elimination of lofexidine, but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in mild, moderate, and severe hepatically impaired subjects to subjects with normal hepatic function (6 subjects in each hepatic function group), mean C_max values were similar for subjects with normal, mild, and moderate hepatic impairment as shown in the following table.

Lofexidine Pharmacokinetics in Subjects with Hepatic Impairment:

Renal Impairment

Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 8 end-stage renal disease subjects on 3 times weekly hemodialysis to 8 subjects with normal renal function matched for sex, age, and body mass index, mean C_max values were similar for end-stage renal disease and normal renal function subjects, indicating no change in maximum lofexidine exposure with renal impairment as shown in Table 7.

The impact of dialysis on the overall pharmacokinetics of lofexidine during a typical 4-hour dialysis was minimal; the drop in lofexidine plasma concentrations produced during the dialysis session was transient, with a rebound to nearly predialysis concentrations after re-equilibration within a few hours following completion of the dialysis cycle.

In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 6 subjects each with normal renal function, mild renal impairment, and moderate renal impairment as well as 5 subjects with severe renal impairment but not requiring dialysis, there were similar increases in mean C_max values in subjects with mild and moderate renal impairment in comparison to subjects with normal renal function with additional increase in mean C_max values in subjects with severe renal impairment. Mean AUC_last, AUC_∞, and t_1/2 increased with severity of renal impairment as shown in the following table.

Lofexidine Pharmacokinetics in Subjects with Renal Impairment:

Drug Interaction Studies

Lofexidine coadministered with methadone

In a double-blind placebo-controlled study of 23 patients maintained on a methadone dose of 80-120 mg/day and concomitantly administered lofexidine up to 2.88 mg/day, lofexidine did not alter the pharmacokinetics of methadone. Lofexidine concentrations may be slightly increased when coadministered with methadone; however, the increase at concentrations expected with recommended dosing is not clinically meaningful.

Lofexidine coadministered with buprenorphine

In a double-blind placebo-controlled study of 30 subjects maintained on buprenorphine (16-24 mg/day) concomitantly administered lofexidine up to 2.88 mg/day, no pharmacokinetic or pharmacodynamic interactions between lofexidine and buprenorphine were seen.

Lofexidine coadministered with oral naltrexone

In an open-label, single-arm study of 24 healthy subjects, oral naltrexone (50 mg/day) did not significantly alter the single-dose pharmacokinetics of lofexidine (0.36 mg). The alteration in steady-state pharmacokinetics of oral naltrexone was statistically significant in the presence of lofexidine. The t_max was delayed for both naltrexone and 6ß-naltrexol (2-3 hours), and overall exposure was slightly reduced when naltrexone was administered with lofexidine.

Lofexidine coadministered with paroxetine

In an open-label, single-sequence study of 24 healthy subjects, the strong CYP2D6 inhibitor paroxetine (40 mg/day) increased lofexidine (0.36 mg) C_max and AUC_∞ by approximately 11% and 28%, respectively.