A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Figure 1

Improvement in characteristic erythematous epoprostenol rash in subject 4. At baseline (left) and after 119 days (16 weeks) of sorafenib administration (right).

Figure 2

Systemic blood pressure changes. Changes in mean systolic (upper curve) and mean diastolic (lower curve) blood pressure during 16 weeks of therapy with sorafenib. Dotted lines are drawn at baseline values for clarity. DBP, diastolic blood pressure; SBP, systolic blood pressure. Error bars are SEM.

Figure 3

Exercise capacity: results for individual patients. 6MWD, 6-min walk distance; ETT, exercise treadmill test.