Acrivastine, a structural analog of triprolidine hydrochloride, exhibits H1-antihistaminic activity in isolated tissues, animals, and humans, and has sedative effects in humans (see PRECAUTIONS). The propionic acid derivative of acrivastine is a metabolite in several animal species (as well as in man) and also exhibits H1-antihistaminic activity.
Pseudoephedrine hydrochloride is an indirect sympathomimetic agent; that is, it releases norepinephrine from adrenergic nerves.
In vitro test and in vivo studies in animals of acrivastine and pseudoephedrine in combination failed to demonstrate evidence of any beneficial or deleterious pharmacologic interaction between the two agents.
Pharmacokinetics And Metabolism
Acrivastine was absorbed rapidly from the combination capsule following oral administration and was as bioavailable as a solution of acrivastine. After administration of SEMPREX-D Capsules, maximum plasma acrivastine concentrations were achieved at 1.14 ± 0.23 hour. A mass balance study in 7 healthy volunteers showed that acrivastine is primarily eliminated by the kidneys. Over a 72-hour collection period, about 84% of the administered total radioactivity was recovered in urine and about 13% in feces, for a combined recovery of about 97%. Further, 67% of the administered radioactive dose was recovered in urine as the unchanged drug, 11% as the propionic acid metabolite, and 6% as other unknown metabolites.
Acrivastine exhibits linear kinetics over dosages ranging from 2 to 32 mg t.i.d. The mean ± SD terminal half-life for acrivastine was 1.9 ± 0.3 hours following single oral doses and increased to 3.5 ± 1.9 hours at steady state. The terminal half-life for the propionic acid metabolite was 3.8 ± 1.4 hours. Because of the short half-lives of both acrivastine and its metabolites, accumulation in the plasma following multiple dosing is not expected.
The steady-state maximum acrivastine plasma concentration was 227 ± 47 ng/mL. The oral clearance, and apparent volume of distribution were 2.9 ± 0.7 mL/min/kg and 0.46 ± 0.05 L/kg, respectively, following a single oral dose; oral clearance did not change at steady state (2.86 ± 0.75 mL/min/kg). The apparent volume of distribution increased to 0.82 ± 0.6 L/kg to parallel the increase in the elimination half-life of the drug.
Acrivastine binding to human plasma proteins was 50 ± 2.0% and was concentration-independent over the range of 5 to 1000 ng/mL. The main binding protein was serum albumin although the drug was slightly bound to α-1-acid glycoprotein. No displacement interaction was observed between acrivastine and either phenytoin or theophylline. The binding of acrivastine was not affected by the presence of pseudoephedrine.
Pseudoephedrine hydrochloride was also rapidly absorbed from the combination capsule, and the capsule was as bioavailable as a solution of pseudoephedrine. Steady state maximum plasma concentration for pseudoephedrine was 498 ± 129 ng/mL. The terminal half-life, oral clearance and apparent volume of distribution were 6.2 ± 1.8 hours, 5.9 ± 1.7 mL/min/kg, and 3.0 ± 0.4 L/kg, respectively. Elimination of pseudoephedrine is primarily through the renal route as 55 to 75% of an administered dose appears unchanged in the urine. Pseudoephedrine elimination, however, is highly dependent upon urine pH; the plasma half-life decreased to about 4 hours at pH 5 and increased to 13 hours at pH 8.
Pseudoephedrine did not bind to human plasma proteins over the concentration range of 50 to 2000 ng/mL.
Acrivastine and pseudoephedrine do not influence the pharmacokinetics of the other drug when administered concomitantly.
A single dose pharmacokinetic study showed that the elimination half-lives of acrivastine, the propionic acid metabolite of acrivastine, and pseudoephedrine were prolonged in patients with chronic renal insufficiency. Compared to normal volunteers, the elimination half-life of acrivastine was about 50% increased in patients with mild renal insufficiency (creatinine clearance = 26 to 48 mL/min) and was increased by about 130% in patients with moderate (creatinine clearance = 12 to 17 mL/min) or severe (creatinine clearance 6 to 10 mL/min) renal insufficiency. Oral clearance of acrivastine was diminished by the same magnitude as the half-life was prolonged in each of the three renally impaired groups. The elimination half-life of the propionic acid metabolite of acrivastine was about 140% increased in patients with mild renal insufficiency and about 5 times increased in patients with moderate or severe renal insufficiency.
Compared to normal volunteers, the elimination half-life of pseudoephedrine was about 3 times increased in patients with mild renal insufficiency, about 7 times increased in patients with moderate renal insufficiency, and about 10 times increased in patients with severe renal insufficiency. Oral clearance of pseudoephedrine was diminished by about the same magnitude as the half-life was prolonged in each of the three renally impaired groups (see PRECAUTIONS, Use In Patients With Diminished Renal Function).
The total body load removed by dialysis is approximately 20%, 27% and 38% for acrivastine, the propionic acid metabolite of acrivastine, and pseudoephedrine, respectively, and therefore, a supplemental dose after a dialysis session is not required.
Based on a multiple dose cross study comparison, the apparent volume of distribution for acrivastine was 44% lower in elderly (n = 36, 65-75 yr) than in young volunteers (n = 16, 19-33 yr). This difference could be attributed to the decrease in total body water that occurs with aging. Despite this difference, no appreciable differences in plasma acrivastine concentrations were seen in the elderly compared to the young, and no appreciable accumulation of acrivastine occurred in plasma at steady-state. The elimination half-life for pseudoephedrine was 18% longer in elderly (7.9 hours) than in younger subjects (6.7 hours), presumably due to the decline in average renal function that occurs with aging. Despite this difference, clearance of pseudoephedrine was not appreciably different in elderly and younger subjects. Elderly patients can therefore be given the same dosage as younger patients. SEMPREX-D Capsules are not recommended, however, in patients with renal impairment (see PRECAUTIONS, Use In Patients With Diminished Renal Function and Geriatric Use).
The effect of age and sex on the pharmacokinetic parameters of acrivastine and pseudoephedrine was determined in 93 healthy volunteers who participated in various studies. All of the 93 volunteers were Caucasian (81 males and 12 females); 57 were between the ages of 18 and 38 years and 36 were between the ages of 65 and 75 years. There were no age- or sex-related differences in the pharmacokinetic parameters of either acrivastine or pseudoephedrine.
The effect of race on acrivastine and pseudoephedrine pharmacokinetics was examined by screening data obtained from 1035 patients, age 12 to 71 years, who participated in the eight safety and efficacy studies. No race-related differences were observed in the pharmacokinetics of either acrivastine or pseudoephedrine.