Treprostinil

Treprostinil is a prostacyclin analogue. It exerts a direct vasodilation effect on the pulmonary and systemic arterial circulation and, inhibits platelet aggregation.

Distribution

In humans, steady-state plasma concentrations are usually achieved within 15 to 18 hours of the initiation of either subcutaneous or intravenous infusion of treprostinil. Steady-state plasma concentrations of treprostinil are dose-proportional at infusion rates of 2.5 up to 125 ng/kg/min.

The mean apparent elimination half-life following subcutaneous administration ranged from 1.32 to 1.42 hours after infusions over 6 hours, 4.61 hours after infusions over 72 hours, and 2.93 hours after infusions lasting at least three weeks. The mean volume of distribution for treprostinil ranged from 1.11 to 1.22 l/kg, and plasma clearance ranged from 586.2 to 646.9 ml/kg/h. Clearance is lower in obese subjects (BMI >30 kg/m²).

In a seven-day chronic pharmacokinetic study in 14 healthy volunteers with treprostinil doses ranging from 2.5 to 15 ng/kg/min administered by subcutaneous infusion, steady state plasma treprostinil concentrations reached peak levels twice (at 1 a.m. and 10 a.m. respectively) and trough levels twice (at 7 a.m. and 4 p.m. respectively). The peak concentrations were approximately 20% to 30% higher than the trough concentrations.

Elimination

In a study conducted on healthy volunteers using [¹⁴C] radioactive treprostinil, 78.6% and 13.4% of the subcutaneous radioactive dose were recovered in the urine and faeces respectively over a period of 224 hours. No single major metabolite was observed. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for a combined total of 64.4%. Three are products of oxidation of the 3-hydroxyloctyl side chain, one is a glucuroconjugated derivative (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dose was recovered in the urine as unchanged parent drug.

An in vitro study demonstrated no inhibitory potential of treprostinil to human hepatic microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A).

Moreover, administration of treprostinil had no inducing effect on hepatic microsomal protein, total cytochrome (CYP) P 450 content or on the activities of the isoenzymes CYP1A, CYP2B and CYP3A.

Hepatic Insufficiency

In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, treprostinil at a subcutaneous dose of 10 ng/kg/min for 150 minutes had an AUC_0-24h that was increased 260% and 510%, respectively, compared to healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults.

Elderly patients

In a multivariate analysis of pooled studies, patients in the age group ≥65 years had a small reduction in plasma clearance of treprostinil. However, most publications regarded either healthy volunteers or patient with PAH. CTEPH patients were rarely described. Age stratification was not performed in any publication. As only few studies reported on PK parameters but none reported both on CTEPH indication and PK data, no information is available on the pharmacokinetics of treprostinil in elderly patients.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.

In 13 and 26 week studies continuous subcutaneous infusions of treprostinil sodium caused infusion site reactions in rats and dogs (oedema/erythema, masses/swellings, pain/sensitivity to touch). In dogs severe clinical effects (hypoactivity, emesis, loose stool and infusion site oedema) and death (associated with intestinal intussusceptions and rectal prolapse) were observed in animals administered ≥300ng/kg/min. Mean steady state plasma treprostinil levels of 7.85ng/ml were measured in these animals. Plasma levels of this order may be achieved in humans treated with treprostinil infusions at >50ng/kg/min.

As a continuously sufficient exposure to treprostinil has not been proven for any dosage tested in the reproductive studies in rats, these studies might be insufficient regarding possible effects on fertility, prenatal and postnatal development.

No long-term animal studies have been performed to evaluate treprostinil’s carcinogenic potential.