A Pharmacokinetics Study for Pediatric Participants With Pulmonary Arterial Hypertension

• Pharmacokinetics: Area under the concentration time curve for tadalafil [ Time Frame: Period 1: pre dose up to 24 hours post dose ] [ Designated as safety issue: No ]
• Pharmacokinetics: Maximum plasma concentration for tadalafil [ Time Frame: Period 1: pre dose up to 24 hours post dose ] [ Designated as safety issue: No ]

• Change from baseline to endpoint in World Health Organization (WHO) functional class [ Time Frame: Period 1: baseline, 10 weeks ] [ Designated as safety issue: Yes ]
• Change from baseline to endpoint in 6 minute walk distance for participants greater than or equal to 7 years of age [ Time Frame: Period 1: baseline, 10 weeks ] [ Designated as safety issue: Yes ]
• Percent increase from baseline to endpoint in N Terminal-Pro Brain Natriuretic Peptide (NT-Pro-BNP) [ Time Frame: Period 1: baseline and 10 weeks ] [ Designated as safety issue: Yes ]
• Percentage of participants with clinical worsening [ Time Frame: Period 2: baseline up to 2 years ] [ Designated as safety issue: Yes ]

The purpose of this study to see how much study drug is in the blood after dosing children with pulmonary arterial hypertension (PAH) and to establish the correct dose for further clinical research.

During Period I, tadalafil will be administered orally, once daily, at a low dose for approximately 5 weeks followed by a high dose for approximately 5 weeks. Dose levels are calculated based on body weight cohorts. Heavy weight cohort >=40 kg, middle weight cohort >=25 kg to <40 kg. Light weight cohort<25 kg. Participants who complete Period 1 may continue taking tadalafil in Period 2 for at least 2 years. Starting dose will not exceed the maximum weight range dose established in Period 1 and may be adjusted based on available safety and efficacy information.

Inclusion Criteria:

• Currently have a diagnosis of PAH that is either:

  • idiopathic (including hereditary), related to collagen vascular disease, related to anorexigen use, associated with surgical repair, of at least 6 month duration, of a congenital systemic to pulmonary shunt (for example, atrial septal defect, ventricular septal defect, patent ductus arteriosus).
• Have a history of the diagnosis of PAH established by a resting mean pulmonary artery pressure ≥25 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and a pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. In the event that a pulmonary artery wedge pressure is unable to be obtained during right heart catheterization, participants with a left ventricular end diastolic pressure <15 mm Hg, with normal left heart function, and absence of mitral stenosis on echocardiography can be eligible for enrollment
• Have a World Health Organization (WHO) functional class value of I, II or III at the time of enrollment

Exclusion Criteria:

• Have pulmonary hypertension related to conditions other than specified above, including but not limited to chronic thromboembolic disease, portal pulmonary hypertension, left-sided heart disease or lung disease and hypoxia

• History of left-sided heart disease, including any of the following:

  • clinically significant (pulmonary artery occlusion pressure [PAOP] 15 to 18 mm Hg) aortic or mitral valve disease (that is, aortic stenosis, aortic insufficiency, mitral stenosis, moderate or greater mitral regurgitation)
  • pericardial constriction
  • restrictive or congestive cardiomyopathy
  • left ventricular ejection fraction <40% by multigated radionucleotide angiogram (MUGA), angiography, or echocardiography
  • left ventricular shortening fraction <22% by echocardiography
  • life-threatening cardiac arrhythmias
  • symptomatic coronary artery disease within 5 years of study entry as determined by the physician
• History of atrial septostomy or Potts Shunt within 3 months before administration of study drug
• Unrepaired congenital heart disease