Candice Jamois

First approval of rituximab in pediatrics with Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA): Population PK and exposure-response analyses, key elements of the full extrapolation strategy from adults to 2 to 17 years old patients.

Candice Jamois (1), Jacques Gaudreault (2), Clarisse Chavanne (1), Melissa Cheu (3), and Leonid Gibiansky (4).

(1) Clinical Pharmacology, Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel.

Objectives:

GPA and MPA are systemic autoimmune conditions affecting blood vessels. B cells may contribute to GPA and MPA pathogenesis.1,2 Rituximab (Rituxan/MabThera®, RTX), a monoclonal antibody (mAb) specific for the CD20 antigen on the surface of B cells, is approved for treating adults with GPA and MPA based on the results of RAVE (Induction)3 and Mainritsan (Maintenance)4 Phase III trials.  This work reports the investigations conducted to establish safety and efficacy of rituximab in pediatric patients with GPA and MPA.

Methods:

The pediatric approval was based on Study WA25615 (PePRS) in 25 pediatric patients with active GPA or MPA. PK-PD modeling supported a full extrapolation strategy from adults to pediatrics. First, an adult population PK model was updated with pediatric data to support the ‘matching exposure strategy’. Second, similar mode of action and exposure-response (ER) relationships were shown between children and adults.  Finally, simulations supported the extrapolation to children from 2 to < 6 years old (yo), age group not included in the trial, and a proposal for a standardized maintenance regimen in pediatrics. 

A total of 691 samples from 122 patients (97 from RAVE and 25 from PePRS) who received at least 4 weekly RTX IV doses of 375 mg/m2 were included in the popPK analysis using NONMEM6. Median (range) age and BSA of 25 pediatric patients were 14 (6-17) years and 1.45 (0.88-1.9) m2. Cumulative area under the concentration-time curve over the six-months Induction (AUC0-180) estimated using actual dosing history and individual PK parameters was used to assess (1) similarity in exposure between children and adults and (2) the relationships between exposure and B-cells response, -probability of Month 6 remission, and -probabilities of occurrence of adverse events.  

In addition, simulated RTX exposure was compared between adult and pediatric patients. In adults, exposure was computed using the individual PK parameters of 94 Adults patients from RAVE. For children, a similar sample size of 94 subjects was simulated for each of the following BSA values: 0.5, 0.8, 1.2 and 1.8 m2, corresponding to the typical values for a 2, 6, 12 and 18 yo children respectively7. The individual PK parameters of those patients were simulated using the between-patient variabilities of the popPK model. Similarly, different follow-up doses (i.e.: twice 250, 275 and 300 mg/m2 administered 2 weeks apart) in pediatric patients were simulated to determine which dose would best match the adult exposure for the approved follow-up dose of  twice 500 mg administered 2 weeks apart4. 

Results:

A linear 2-compartment model described RTX PK.  For a typical patient (BSA=1.9 m2 without ADA), clearance (CL) (258 mL/day), inter-compartment clearance (317 mL/day), central volume  (Vc) (3070 mL), peripheral volume (4160 mL), and terminal half-life (25.6 days) were in the typical range for mAbs. CL increased with BSA (power 0.952) and was 38.2% higher in patients with ADA. 

In both adults and pediatrics, RTX induced a rapid and prolonged B-cell depletion across the whole range of exposure with B-cell depletion lasting longer in patients with higher exposure. The magnitude of the depletion and the start time of repletion were comparable between adult and pediatrics. Similar to adults, no association was found between variability in exposure and clinical efficacy and safety endpoints in pediatrics, suggesting the Induction regimen resulted in exposure at the plateau of the ER relationship.

Known features of FcRn8,9 and IgG biology in children10,11, the strong relationship between RTX CL and BSA, with similar AUC0-180 in children compared to adults across the entire range of BSA and supportive PK simulations suggested that RTX disposition  in ≥ 2 to< 6 yo pts is expected to be similar to the one assessed in children >6 yo. In addition, simulations showed that 250 mg/m2 dosing regimen given to children is expected to result in comparable exposure to adults treated with the approved 500 mg dose. 

Conclusions:

In summary, this work supported the regulatory approval of the first pediatric indication for MabThera/Rituxan. An induction regimen of four weekly IV infusions of 375 mg/m2 is recommended in children >2 years of age with GPA or MPA, in United States (US) and Europe. A follow-up dosing regimen consisting of two 250 mg/m2 IV infusions separately by two weeks, followed by a 250 mg/m2 IV infusion every 6 months, is also approved in the US.

References:

  1. Martin F, Chan AC. Pathogenic roles of B cells in human autoimmunity; insights from the clinic. Immunity., 2004; 20(5):517-527.
  2. Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Differential B- and T-cell activation in Wegener’s granulomatosis. J Allergy Clin Immunol. 1999;103(5 Pt 1):885-894.
  3. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.
  4. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. New Engl J Med. 2014;371(19):1771-1780.
  5. Mulugeta Y, Barrett JS, Nelson R, et al. Exposure matching for extrapolation of efficacyin pediatric drug development. J Clin Pharm 2016; 56(11):1326−34.
  6. Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides (1989-2015). Ellicott City, Maryland, USA: Icon Development Solutions; 2015.
  7. CCLG – Chemotherapy Standardisation Group 2008 Estimation of Body-Surface Area in Infants and Children* – https://www.ouh.nhs.uk/oxparc/professionals/documents/BodysurfaceareaCCLGChart1.pdf
  8. Israel EJ, Taylor S, Wu Z, et al. Expression of the neonatal Fc receptor FcRn, on human intestinal epithelial cells. Immunology 1997; 92:69−74.
  9. Shah U, Dickinson BL, Blumberg RS, et al. Distribution of the IgG Fc receptor, FcRn, inthe human fetal intestine. Pediatr Res 2003; 53(2):295−301.
  10. Stoop JW, Zegers BJM, Sander PC, et al. Serum immunoglobulin levels in healthychildren and adults. Clin. Exp. Immunol. 1969; 4: 101-112.
  11. Belldegrin A, Shoenfeld Y, Pick AI, et al. Age related distribution of serumimmunoglobulin concentration in 1003 healthy children and adults. Biomedicine, 1980; 33, 8-12. 

Reference: PAGE () Abstr 9578 [www.page-meeting.org/?abstract=9578]

Poster: Oral: Other Topics