Bosentan (Tracleer (R)) is an orally administered dual endothelin-1 (ET-1) receptor antagonist approved for use in patients with WHO class 11 (mildly symptomatic) pulmonary arterial hypertension (PAH). Oral bosentan therapy was beneficial and generally well tolerated in patients with mildly symptomatic PAH. In a well designed, placebo-controlled trial in adolescents and adults with mildly symptomatic PAH, pulmonary vascular resistance was significantly reduced with bosentan relative to placebo, but the 6-minute walk distance did not increase significantly. Similarly, pediatric patients (most of whom had mildly symptomatic PAH) in a small uncontrolled trial experienced some improvement in hemodynamic variables with bosentan, but did not experience a significant increase in exercise capacity. Adverse events associated with bosentan were consistent with those seen in other indications, with major concerns being the potential for teratogenicity and hepatotoxicity, for which regular liver function monitoring is recommended. Overall, considering the progressive nature of PAH, bosentan extends the treatment options available to patients with mildly symptomatic PAH. Pharmacological Properties Bosentan is a dual ET-1 receptor antagonist that binds competitively and specifically to endothelin A and B receptors, thereby antagonizing the binding of ET-1. Treatment with bosentan improved hemodynamic variables in patients with PAH. The pharmacokinetics of bosentan are dose- and time-dependent; clearance and volume of distribution decrease with increasing intravenous doses and increase with time. In healthy adults, steady state was reached after 3-5 days. The peak plasma concentration of bosentan at steady-state, and its steady-state area under the plasma concentration-time curve from 0 to 24 hours was approximate to 40-60% lower with multiple dose than with single-dose administration, which may be because of dose-dependent auto-induction of metabolizing liver enzymes that peaks after approximate to 4-5 days of administration. Bosentan is metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4 into three metabolites, Ro 48-5033 (major metabolite), Ro 47-8634, and Ro 64-1056. Only Ro 48-5033 is metabolically active, accounting for up to 20% of drug activity. Oral bosentan is eliminated largely via feces in healthy adults, mainly as Ro 48-5033; less than 3% of a dose is excreted in urine. Bosentan has a half-life of 5-7 hours after multiple-dose administration. Compared with healthy adults, patients with PAH may have greater exposure (approximate to 2-fold increase) to bosentan and its active metabolite. The pharmacokinetics of bosentan in pediatric patients with PAH were generally similar to those in healthy adults. However, compared with patients with PAH, steady-state exposure in pediatric patients was 31-61% lower, the reason for which is unclear, but may be attributed to increased metabolism and excretion. As bosentan is both a substrate and an inducer of hepatic CYP2C9 and CYPA34 isoenzymes, it may interact with other drugs that are also substrates, inducers, or inhibitors of these enzymes. Therefore, concomitant use of bosentan with glibenclamide (glyburide), fluconazole, rifampicin (rifampin) [in the EU], and both a CYP3A4 inhibitor and a CYP2C9 inhibitor is not recommended. Bosentan is contraindicated in pregnant women and in child-bearing women who are not using reliable methods of contraception because of an associated risk of teratogenicity and contraception failure. Therapeutic Efficacy Oral bosentan therapy was beneficial in adolescents and adults with mildly symptomatic PAH. In the randomized, double-blind, multicenter, placebo-controlled EARLY trial (n = 185), bosentan 125 mg twice daily for 6 months significantly reduced pulmonary vascular resistance, but there was no significant increase in exercise capacity as assessed by the 6-minute walk distance (co-primary endpoints). Bosentan therapy also significantly improved several other hemodynamic variables and delayed clinical worsening of disease in these patients (secondary endpoints). In addition, in a small, open-label, uncontrolled trial in pediatric patients, most of whom were mildly symptomatic, there was significant improvement from baseline in several hemodynamic variables with bosentan 31.25-125 mg twice daily for 3 months, but there was no significant increase in exercise capacity. Tolerability Bosentan was generally well tolerated in adolescents and adults with mildly symptomatic PAH and in pediatric patients with PAH. Abnormal liver function tests were the most common (>= 5%) treatment-emergent adverse event that occurred at least twice as frequently with bosentan compared with placebo in adolescents and adults with mildly symptomatic PAH during 6 months' therapy in the EARLY trial (8% vs 3%). As with other ET-1 receptor antagonists, bosentan therapy is associated with transient increases in the levels of liver aminotransferases. However, these returned to pre-treatment levels either spontaneously or after dose reduction or discontinuation in clinical trials. Elevations in aminotransferase levels of >3 times the upper limit of normal were reported in 13% of bosentan versus 2% of placebo recipients in adolescents and adults with mildly symptomatic PAH during 6 months' therapy in the EARLY trial. Postmarketing data suggest that the incidence and severity of elevated aminotransferase levels in clinical practice were generally similar to those seen in clinical trials. Treatment with bosentan may also be associated with a decreased hemoglobin levels; in the EARLY trial, 5% of bosentan recipients with mildly symptomatic PAH showed a decrease from baseline in hemoglobin levels during 6 months' therapy, resulting in values of <10 g/dL.
