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

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 I_max 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.

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.. 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.. 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.. 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