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Clinical Trial
. 2023 Jan;63(1):105-118.
doi: 10.1002/jcph.2139. Epub 2022 Sep 11.

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response

Stephen J Balevic  1   2 , Jing Niu  3 , Jianmeng Chen  3 , Dionna Green  4 , Ann McMahon  4 , Christoph P Hornik  1 , Laura E Schanberg  1   2 , Rachel Glaser  5 , Daniel Gonzalez  6 , Gilbert J Burckart  3
Affiliations
Clinical Trial

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response

Stephen J Balevic et al. J Clin Pharmacol. 2023 Jan.

Abstract

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.

Keywords: pediatrics; pharmacodynamics; pharmacokinetics and drug metabolism; regulatory/scientific affairs; rheumatology.

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Conflict of interest statement

Conflict of interest disclosures: SJB receives support from the National Institutes of Health, the US Food and Drug Administration, the Patient-Centered Outcomes Research Institute, the Rheumatology Research Foundation’s Scientist Development Award, the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, and consulting for UCB. LES receives support from CARRA and has research grants from PCORI, BMS and consults for UCB, Sanofi. DG receives research support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD096435-04 and 1R01HD102949-01A1) and from Nabriva Therapeutics through a contract with the University of North Carolina at Chapel Hill. In addition, D.G. serves as a consultant for Tellus Therapeutics, focusing on neonatal drug development. CPH receives salary support for research from National Institute for Child Health and Human Development (NICHD) (R13HD102136; RL1HD107784; R01HD106588), the National Heart Lung and Blood Institute (NHLBI) (R61/R33HL147833), the US Food and Drug Administration (R01-FD006099, PI Laughon; and U18-FD006298), the U.S. government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the non-profit Burrhoughs Wellcome Fund, and other sponsors for drug development in adults and children (https://dcri.org/about-us/conflict-of-interest/

Figures

Figure 1.
Figure 1.. SRI-4 Response in Adult vs. Pediatric Belimumab Studies
A: Overall SRI-4 Response for Belimumab 10 mg/kg IV; B: Overall SRI-4 Response for Placebo; C: Difference in SRI-4 for Belimumab 10 mg/kg vs Placebo. SRI-4, Systemic Lupus Erythematosus Responder Index-4
Figure 2.
Figure 2.. Mycophenolate Exposure and Lupus Disease Activity
Solid black and blue lines represent a Locally Weighted Scatterplot Smoothing (LOESS) fit. AUC, area under the curve; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index. AUC represents the 12-hour AUC.
Figure 3.
Figure 3.. Relationship between Mycophenolic Acid Exposure and SLE Disease Activity
Boxes are mean +/− 1 standard deviation (SD). Whiskers are mean +/− 3x the SD. Active SLE defined a SLEDAI ≥6; Inactive SLE defined as SLEDAI <6. AUC, area under the curve; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index
Figure 4.
Figure 4.. Hydroxychloroquine Exposure and SLE Disease Activity
Hypothesis testing not conducted due to lack of sample size for the pediatric study. Boxes are mean +/− 1 standard deviation (SD). Whiskers are mean +/− 3x the SD. Active SLE defined a SLEDAI ≥6; Inactive SLE defined as SLEDAI <6. SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index
See this image and copyright information in PMC

References

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