Tadalafil - Assess the PK and Safety in Peds Population
|Principal Investigator: Ronald Day|
|Keywords: Tadalafil , PAH , Pediatric , Pulmonary Arterial Hypertension||Department: Pediatric Administration|
|IRB Number: 00061997||Co Investigator: Michael Spigarelli|
|Specialty: Pediatric Cardiology|
Primary Objective: To characterize the pharmacokinetics (PK) of tadalafil in a pediatric population with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further clinical research.
Secondary Objective: To assess the tolerability and safety of tadalafil in a pediatric population with PAH; To compare tadalafil PK profile in a pediatric population with historical adult data from StudyH6D-MC-LVGY; To determine appropriate dose ranges for use in the evaluation of efficacy and safety of tadalafil; To clinically assess the palatability of the tadalafil suspension.
Pulmonary arterial hypertension (PAH) is a rare, chronic, and progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right heart failure and death (Rich 1998; Barst 2004). Pulmonary arterial hypertension can be further classified into idiopathic PAH (IPAH), heritable PAH (FPAH), and associated PAH (APAH). Conditions that are associated with PAH include connective tissue diseases, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV) infection, schistosomiasis and some drugs (particularly anorexigens). The pathogenesis, presentation, diagnosis and management of PAH in children is similar to that in adults, though little research has been conducted in the pediatric population. The prevalence and incidence of PAH is significantly lower in children than in adults (Rubin 1997); it has been estimated that about 0.5 per million children will be diagnosed with IPAH which accounts for about 50% of all pediatric PAH. The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL Registry), a multicenter, observational, US-based registry created to provide the characteristics and treatment patterns of patients with PAH, recently reported just 184 prevalent pediatric cases among 54 enrolling centers in the US (Barst 2008). The sex ratio between female and male is approximately 2:1 in childhood (Badesch et al. 2010) and median survival in children <16 years, prior to the introduction of specific therapies for PAH, was ≤6 months (D’Alonzo et al. 1991; Barst et al. 1999). While sildenafil and bosentan have recently had language added to their labels pertaining to the pediatric population, there remain limited data on the safety and efficacy of the approved adult treatments in a pediatric population. Therapeutic guidelines for children have therefore generally followed those used in adults. Therapies currently approved for the treatment of PAH in adults, in various geographies around the world, include prostacyclin and its analogues (epoprostenol, trepostinil, iloprost, and beraprost), the endothelin receptor antagonists (bosentan and ambrisentan), and the phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil and tadalafil). Tadalafil is an orally administered, potent, and selective PDE-5 inhibitor currently approved in the United States, European Union, Canada and in Japan for the treatment of erectile dysfunction (ED), both on-demand (at doses of 5 mg, 10 mg and 20 mg) and once-daily (at doses of 2.5 mg and 5 mg), and for the treatment of pulmonary arterial hypertension (PAH) (at a dose of 40 mg daily). In adults, tadalafil is rapidly absorbed after oral administration, with maximum concentrations (Cmax) in plasma occurring at a median time of 2 hours. The rate and extent of absorption from tadalafil 10 mg and 20 mg are not influenced by food. Tadalafil is distributed into tissues, with an apparent volume of distribution of 62.6 L. Tadalafil is cleared extensively, with metabolism by cytochrome P450 (CYP) 3A4 being the major pathway. The mean terminal elimination halflife (t½) for tadalafil is 17.5 hours. Tadalafil pharmacokinetics are linear with respect to time and dose over a range of 2.5 to 20 mg. During tadalafil 20 mg once-daily dosing, steady-state plasma concentrations were attained within about 5 days and the degree of drug accumulation was about 1.6-fold. A tadalafil 40 mg single dose is rapidly absorbed, with Cmax in plasma occurring at a median time of 4 hours, and within the range of that reported following a 20 mg single dose. Following tadalafil 40 mg once-daily, the apparent clearance at steady state (CLss/F) and accumulation ratios remained stationary between Day 5 and Day 10. Increases in both Cmax and area under the concentration versus time curve (AUC) are less than proportional as the dose increases from 20 mg to 40 mg. Specifically, due to decreased bioavailability with 40 mg oncedaily doses compared to lower doses, a 2-fold change in dose from 20 mg to 40 mg results in a 48% increase in exposure. The safety and efficacy of tadalafil for the treatment of PAH in adults was investigated in a 16-week placebo-controlled study (Study H6D-MC-LVGY [LVGY]) which demonstrated that, overall, tadalafil 40 mg once-daily dosing was effective in the treatment of patients with PAH and was associated with an increase in exercise capability. Tadalafil 40 mg was well tolerated in the adult PAH patient population with a safety profile similar to that observed in the erectile dysfunction patient population. Population pharmacokinetic (PopPK) data from Study LVGY show that exposure to tadalafil is not influenced by age, cardiovascular conditions, sex, ethnicity, PAH history or duration, creatinine clearance (CC), total serum protein, weight, warfarin, or digoxin, thereby suggesting that tadalafil can be administered without regard to these factors. Concomitant bosentan therapy increased the apparent oral clearance of tadalafil by 75%, resulting in a 35% decrease in exposure in patients receiving 40 mg tadalafil. In patients with PAH not receiving concomitant bosentan, the predicted median tadalafil exposure at steady-state was 26% higher when compared to that in healthy volunteers. There were no clinically relevant differences in mean Cmax compared to healthy volunteers. The results suggest a potentially lower mean clearance of tadalafil in patients with PAH compared to healthy volunteers. An aqueous, ready-to-use suspension for oral administration of 2.0 mg/mL tadalafil has been developed for use in younger children. A relative bioavailability study (Study H6D-MC-LVIF [LVIF]) has been performed in healthy adults to investigate the relative bioavailability of one 20 mg tablet compared to a suspension containing 20 mg tadalafil. Study LVIF also assessed the pharmacokinetics of the tadalafil suspension over the 20 mg to 40 mg dose range. The results from Study LVIF demonstrated that the 20 mg suspension produced a 23% lower Cmax for tadalafil and significant delay in time of maximum observed concentration (tmax) of 1 hour compared to the 20 mg tablet. However, overall exposure to tadalafil was similar for the 20 mg suspension and tablet, with the 90% confidence intervals for the ratios falling within the bioequivalence limits of 0.80 to 1.25. Exposure to tadalafil during the absorption/distribution phase is lower for the 20 mg suspension compared to the 20 mg tablet, with AUC(0-6) and AUC(0-12) being 25% and 16% lower. Results indicated a less-than-dose-proportional increase in tadalafil exposure over the 20 mg to 40 mg dose range for the suspension formulation. Given the efficacy and safety results of tadalafil for the treatment of PAH in adults (Study LVGY), and recognizing the importance of providing prescribers and patients with recommendations reflecting tadalafil experience across developmental stages, Lilly is pursuing the development of tadalafil for the treatment of PAH in patients ≥6 months of age to <18 years of age.
 ≥6 months to <18 years of age (at screening).
 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, patients 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 WHO functional class value of I, II or III at the time of enrollment.
 Patients with PAH either naïve to PAH specific therapy or receiving endothelin receptor
antagonists (ERA). If on an ERA (that is, bosentan or ambrisentan), must be on a
maintenance dose, with no change in dose (other than weight-based adjustments) for
≥12 weeks prior to screening and have a screening aspartate transaminase (AST) or
alanine transaminase (ALT) <3 times the upper limit of normal.
 If on conventional PAH medication, including but not restricted to, calcium channel
blockers, diuretics, digoxin, and oxygen therapy, the patient must be on stable doses with
no changes (other than weight-based adjustments) for at least 4 weeks before screening.
 Have a chest radiograph (CXR) within 6 months of screening that shows clear lung fields
or no more than mild patchy (not diffuse) interstitial infiltrates.
 Female patients of childbearing potential must test negative for pregnancy during
screening. Furthermore, female patients must agree to abstain from sexual activity or to
use a reliable method of birth control as determined by the investigator during the study.
Examples of reliable birth control methods include true abstinence as a lifestyle choice
(periodic sexual abstinence method is not acceptable); the use of oral contraceptives; a
reliable barrier method of birth control (diaphragms with contraceptive jelly; cervical caps
with contraceptive jelly; condoms with contraceptive foam; intrauterine devices).
 Written informed consent from parents or guardians (and written assent from
appropriately aged patients) will be obtained prior to any study procedure being
Patients will be excluded from study enrollment if they meet any of the following criteria:
 Have pulmonary hypertension related to conditions other than specified above, including
but not limited to chronic thromboembolic disease, portal pulmonary hypertension, leftsided
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 Potts Shunt within 3 months before administration of study drug.
 Unrepaired congenital heart disease.
 Concurrent PDE-5 inhibitor therapy (sildenafil or vardenafil) or has received PDE-5
inhibitor therapy within 24 hours prior to the first study drug dosing (baseline visit).
 Concurrent therapy with prostacyclin or its analogues.
 Commence or discontinue a conventional PAH medication including but not restricted to:
calcium channel blockers, diuretics, anti-coagulants, digoxin, and oxygen therapy within
4 weeks prior to screening.
 Have a history of angina pectoris or other condition that was treated with long- or shortacting
nitrates within 12 weeks before administration of study drug.
 Currently receiving treatment with doxazosin, nitrates or cancer therapy.
 Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease
inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent
CYP3A4 inducers, such as rifampicin.
 Are nursing or pregnant.
 Have a WHO functional class value of IV at the time of enrollment.
 Have severe hepatic cirrhosis, Child-Pugh Grade C.
 Have severe renal insufficiency, defined as receiving renal dialysis or having a measured
or estimated creatinine clearance (CC) 30 mL/min 1.73 m2 (Schwartz Formula):
All Females and Pre-adolescent Males:
Ccr (mL/min/1.73 m2) = 0.55 × Height (cm) / SCr (mg/dL)
Ccr (mL/min/1.73 m2) = 0.70 × Height (cm) / SCr (mg/dL)
Where Ccr is Creatinine Clearance and SCr is Serum Creatinine
 Have severe hypotension or uncontrolled hypertension as determined by the Investigator.
 Diagnosed with a retinal disorder (for example, hereditary retinal disorders, retinopathy of
the preterm and other retinal disorders)
 Have significant parenchymal lung disease.
 Have bronchopulmonary dysplasia.
 Have hemoglobinopathies.
 Have a history of drug, alcohol, or substance abuse within the past 6 months or present
use, as assessed by the investigator.
 Have previously completed or withdrawn from this study (Study LVIG), or any other
study investigating tadalafil.
 Have previously taken tadalafil within 90 days prior to the first study drug dosing (Day 1,
Visit 2) or are hypersensitive to tadalafil.
 Unable to take orally administered tablet (without chewing, crushing or breaking) or
 Investigator site personnel (or their immediate family) directly affiliated with this study .
Immediate family is defined as a spouse, parent, child or sibling, whether biological or
 Are Lilly employees, (that is, employees, temporary contract workers, or designees
responsible for the conduct of the study). Immediate family of Lilly employees may
participate in Lilly-sponsored clinical trials, but are not permitted to participate at a Lilly
facility. Immediate family is defined as a spouse, parent, child or sibling, whether
biological or legally adopted.
 Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial
involving an investigational drug or device or off-label use of a drug or device, or
concurrently enrolled in any other type of medical research judged not to be scientifically
or medically compatible with this study by the Sponsor.
 Are allergic to any of the excipients, notably lactose.
 Currently receiving treatment with soluble guanylate cyclase stimulator therapy (such as riociguat).