Dose Recommendation and Risk/Beneft Assessment o f Revatio in Pediatric Pulmonary Arterial Hypertension Using a Modelling and Simulation Approach Lutz Harnisch, 1 Xiang Gao, 2 Pascal Chanu 3 1 Pfzer Inc, Pharmacometrics, Sandwich, UK; 2 Pfzer Inc, Clinical Pharmacology, Groton, CT, USA; 3 Pharsight Consulting Services™, a division of Certara™, St. Louis, MO, USA European Society of Cardiology August 25–29, 2012 Munich, Germany 302 Background 7 Effective and safe therapy is needed to increase the functional capacity, quality of life, and survival of pediatric patients with pulmonary arterial hypertension (PAH). 7 A major challenge is to determine appropriate dosing and assess safety in pediatric PAH patients with growing lungs. 1 – Dosing recommendations regarding optimal treatment of pediatric patients require controlled pediatric-specific pharmacokinetic (PK), pharmacodynamic (PD; eg, hemodynamic, clinical endpoint), and long-term safety data. 1 – However, PAH is even rarer in children than in adults, making it difficult to obtain controlled data to direct treatment. 7 The phosphodiesterase type 5 inhibitor sildenafil (REVATIO ® ; Pfizer Inc) 20 mg administered 3 times daily (TID) is approved for the treatment of PAH in adults. – 2 randomized, double-blind clinical trials in adult patients showed significantly improved exercise capacity, hemodynamic parameters, and health-related quality of life with sildenafil vs placebo. 2,3 7 Sildenafil is approved in the European Union for the treatment of PAH in children. – The 16-week, randomized, double-blind study, Sildenafil in Treatment-Naive Children, Aged 1–17 Years, With Pulmonary Arterial Hypertension (STARTS-1), assessed the effects of low (10 mg TID), medium (10, 20, or 40 mg TID depending on body weight), and high (20, 40, or 80 mg TID depending on body weight) doses of sildenafil in treatment-naive pediatric patients with PAH. 4 – Improvement in the primary endpoint of peak oxygen consumption (VO2peak) was marginally significant for the 3 sildenafil dose groups combined compared with placebo. – Improvements in exercise capacity, World Health Organization functional class, and hemodynamics were observed with medium- and high-dose sildenafil compared with placebo; sildenafil was well tolerated. 7 A population approach discussed elsewhere has modelled the sildenafil PK-PD data (VO2peak and pulmonary vascular resistance index [PVRI]) and quantified the relationship between dose exposure and outcome measures. 5 – The target PVRI response can be related to a change in VO2peak for those children who can perform the exercise capacity test. However, the target PVRI effect applies to all children, regardless of their ability to perform that test. Purpose 7 Here, using data from the STARTS-1 trial, simulations across a modeling framework on dosing schemes, sildenafil exposure, hemodynamics, and clinical endpoints for a representative PAH population were used to make dose recommendations for sildenafil in the treatment of pediatric PAH patients. 7 To underpin the beneficial effect of the selected dose regimen, a US Food and Drug Administration (FDA) model that relates adult outcome measures was put into the context of the sildenafil pediatric data, based on an FDA advisory committee’s discussion of PVRI as an additional endpoint in the assessment of PAH treatment responses. 6 Models 7 A population PK model, 7 a population PK-PD model for VO2peak, 5 and a population PK-PD model for pulmonary vascular resistance (PVR), 5 were used for simulation to evaluate dosing regimens for the pediatric population. – Assuming the clinical benefit of improvement in VO2peak and PVR, the PK-PD models derived from the pediatric and adult data allow assessment of the performance of various proposed dosing regimens for their ability to achieve target endpoints. 7 2 simulation schemes were implemented across the weight range from 8–80 kg, the first based on a fixed milligram dose regimen (2–80 mg) and the second based on a variable mg/kg dose (0.25–1.25 mg/kg). 7 2 promising dosing regimens were selected and compared for their PVRI 5 and VO2peak response to the labeled adult dose of 20 mg TID. 7 A target sildenafil concentration and the clinical relevant PVRI 5 and VO2peak target responses were used to select the recommended dose regimen Results 7 Pediatric sildenafil data appear consistent with the model and achieve the target PVRI response (Figure 1). Medium- and high-dose regimens achieve the target PVRI effect. Figure 1. Prediction Interval Constructed From the FDA Model Projecting the Responses From the Pediatric Sildenafl Data SIL low dose SIL medium dose SIL high dose Placebo-Corrected Change From Baseline in Exercise Capacity, % Placebo-Corrected Change From Baseline in PVRI, % 20 0 –10 –20 –10 –20 –30 0 –50 –60 –40 10 10 FDA=US Food and Drug Administration; PVRI=pulmonary vascular resistance index; SIL=sildenafl. 7 PK-PD models reported earlier relate exposure to exercise capacity (VO2peak or 6MWD) and PVR responses across adults and children. 7 The proportion of patients predicted to achieve the threshold response of ≥10% improvement in VO2peak is shown in Figure 2. 20% of placebo patients are predicted to respond, regardless of weight. The predicted responder rate is 47% for doses of 40 mg TID and 80 mg TID, regardless of weight, but is weight dependent for doses of 10 mg TID and 20 mg TID . Figure 2. Proportion of Population Predicted to Attain a ≥10% Improvement in VO2peak for Various Sildenafl Doses 10 20 25 30 35 Patients Predicted to Attain a ≥10% Improvement in VO2peak, % Weight, kg 40 45 SIL 30 mg SIL 40 mg SIL 80 mg 20 30 40 PLC SIL 10 mg SIL 20 mg PLC=placebo; SIL=sildenafl; VO2peak=peak oxygen consumption. 7 Because a weight-normalized dosing regimen is often used in pediatrics, similar simulations were performed assuming sildenafil dosages of 0.25–1.25 mg/kg across a wide weight range (Figure 3). Figure 3. Proportion of Population Predicted to Attain a ≥10% Improvement in VO2peak for Various Weight-Normalized Sildenafl Doses 10 20 25 30 35 Patients Predicted to Attain a ≥10% Improvement in VO2peak, % Weight, kg 40 45 SIL 0.75 mg/kg SIL 1.00 mg/kg SIL 1.25 mg/kg 20 30 40 PLC SIL 0.25 mg/kg SIL 0.33 mg/kg SIL 0.50 mg/kg PLC=placebo; SIL=sildenafl; VO2peak=peak oxygen consumption. 7 A singular mg/kg dosing regimen of up to 1 mg/kg did not reach a consistent responder rate across the weight range in pediatric patients with PAH; thus, that approach was abandoned. L.H. and X.G. are Pfzer employees and hold shares of Pfzer stock. P.C. is an employee of Pharsight Consulting Services™, who were paid consultants to Pfzer in connection with the development of this manuscript. This study was sponsored by Pfzer Inc. Editorial/medical writing support was provided by Deborah M. Campoli-Richards, BSPharm, RPh, of Complete Healthcare Communications, Inc., and was funded by Pfzer Inc. References 1. Barst RJ. Heart. 2010;96(17):1337-1338. 2. Galie N, et al. N Engl J Med. 2005;353(20):2148-2157. 3. Simonneau G, et al. Ann Intern Med. 2008;149(8): 521-530. 4. Barst RJ, et al. Circulation. 2012;125(2):324-334. 5. Chanu P, et al. A dose selection rationale based on hemodynamics for sildenafil in pediatric patients with pulmonary arterial hypertension (PAH). Presented at: Population Approach Group in Europe Annual Meeting; June 7-10, 2011; Athens, Greece. 6. Brar S. Use of Change in PVRI for Dosing Recommendations of Adult-Approved Drugs in Pediatric PAH Patients. FDA-CDER-CDRAC, 29th July 2010. 7. Watt S, et al. Population pharmacokinetics of sildenafil in paediatric and adult patients with pulmonary arterial hypertension. Presented at: the European Society of Cardiology; August 28-September 1, 2010; Stockholm, Sweden. Discussion/Conclusion 7 The association of treatment responses between the VO2peak and PVRI endpoints shows consistency with an FDA model, which supports using these endpoints for pediatric dose selection. 7 A dosing regimen of 10 mg for children weighing up to 20 kg and 20 mg for children weighing more than 20 kg is predicted to result in a sufficiently high responder rate on VO2peak in children aged 7–17 years. 7 This recommended dose regimen applied to children aged 1–17 years is also predicted to result in a PVR response similar to or better than that seen at the labeled adult dose of 20 mg TID. 7 The evaluation of fixed milligram–based doses against the threshold average steady-state concentration at which 90% of the maximum effect in VO2peak would be attained led to 2 dose regimens (Figure 4). – A lower regimen (10/20 mg) consisting of 10 mg TID for children ≤20 kg body weight and 20 mg TID for children weighing >20 kg – A higher regimen (20/40 mg) consisting of 20 mg TID for children ≤20 kg body weight and 40 mg TID for children weighing >20 kg 7 The 10/20-mg dose regimen would achieve the desired clinical response on VO2peak, and the 20/40-mg dose regimen would add little clinical benefit (Figure 5). 7 The assessment of PVR across the adult and pediatric weight range shows that the proposed 10/20-mg dose regimen produces a similar or better and clinically beneficial PVR response compared with the labeled dose of 20 mg TID in adults (Figure 6). Figure 4. Relation Between Body Weight and Average Concentration at Steady State for Each Dose Regimen 100 200 300 Average Concentration at Steady State, ng/mL Weight, kg 400 80 40 20 60 80 40 20 60 SIL 20/40 mg SIL 10/20 mg Prediction interval (PI) for 2 dosing regimens. Red line shows the population mean; black lines show the 90% PI; dashed line shows the concentration at 90% of maximum effect at 31.32 ng/mL (point estimation without uncertainty) as derived in the pharmacokinetic/pharmacodynamic VO2peak model. SIL=sildenafl. Figure 5. Proportion of Population Predicted to Attain a ≥10% Improvement in VO2peak for the 10/20-mg and 20/40-mg Dose Regimens Across Weight Range 10 20 25 30 35 Patients Predicted to Attain a ≥10% Improvement in VO2peak, % Weight, kg 40 45 PLC SIL 10/20 mg SIL 20/40 mg 20 30 40 PLC=placebo; SIL=sildenafl; V02peak=peak oxygen consumption. Figure 6. Proportion of Population Predicted to Attain a ≥20% Improvement in PVR for the 10/20-mg and the 20/40-mg Dose Regimens Across Weight Range 0 0 20 40 60 Patients Predicted to Attain a ≥20% Improvement in PVR, % Weight, kg Non-developmentally Able Children and Those With a Shunt 80 100 20 40 60 80 0 0 20 40 60 Patients Predicted to Attain a ≥20% Improvement in PVR, % Weight, kg Developmentally Able Children 80 100 20 40 60 80 Blue line=sildenafl 10/20-mg TID dose regimen; green line=sildenafl 20/40-mg TID dose regimen; red line=placebo; dashed line=responder rate for adult PAH patients at the labeled dose of sildenafl 20 mg TID; PVR=pulmonary vascular resistance; TID=3 times daily. View publication stats View publication stats