Pharmacokinetic Studies of IGIV

Our pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn web:www.medicilon.com

1. Guidance for Pharmacokinetic (PK) Studies

We recommend that you submit PK data in your BLA to describe the distribution, metabolism, and elimination of IGIV products. These data will provide a basis for historical comparison between the investigational IGIV product and licensed IGIVs, as well as help determine the optimum dosing schedule for the product. We recommend that you obtain PK data from at least 18-20 adult subjects with primary humoral immune deficiency (either previously untreated or previously treated patients). PK parameters should be calculated for the overall PK study subject cohort, as well as for subgroups according to IGIV infusion dosing schedule (e.g., subjects dosed every 3 versus every 4 weeks). You may obtain the data as part of the Phase 3 clinical trials conducted to establish efficacy and safety. Suitable PK studies can be single arm studies compared with historical data or they can be either crossover or parallel studies if you choose to include a licensed product arm as a positive control. If you use the historical control approach, your PK study should be part of a single arm 12-month Phase 3 study in which the following measurements should be included: • The steady-state trough total IgG levels obtained from the previously used IGIV. • Sufficient plasma total IgG and selected specific (e.g., antipneumococcal capsular polysaccharide and anti-Haemophilus influenzae) antibody levels to derive a plasma concentration-time curve, half-life, area under the curve (AUC0-t; AUC0-infinity), volume of distribution, concentration maximum (Cmax), and elimination rate constant(s). The serum samples for these antibody measurements should be made after a “washout” period lasting 3 to 5 estimated halflives, during which time subjects receive the investigational IGIV on a regular basis. You should justify the choice of PK model used to derive the PK parameters. • You should measure the trough total IgG levels prior to each infusion during the study. IgG subclass levels should be measured at least once after steady state is estimated to have been achieved (i.e., after approximately 5 half lives have elapsed during regular periodic administration of the test product). It may be appropriate to identify in the study protocol and provide justification for the minimum trough level value that is acceptable. Your study report should include the proportion of subjects who failed to meet the target trough level at any time point equal to or subsequent to 5 estimated half-lives. If you elect Contains Nonbinding Recommendations not to include a concurrent control for your PK study/sub-study design, we recommend you compare and relate your observed trough IgG level data to that of currently licensed historical control IGIV products. • You should develop a prospective plan for defining the recommended dosing schedule based on the observed/calculated PK parameters and include the plan in the PK study protocol. For patients who are previously untreated, we recommend you determine the time to reach steady state.

2. PK Studies in the Pediatric Population The following definitions of pediatric populations are described in the FDA guidance entitled “General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products” (Ref. 5). • Neonate: birth to 1 month • Infant: 1 month to 2 years • Child: 2 to 12 years • Adolescent: 12 years to <16 years If possible and needed, the PK study of an IGIV product should be conducted across all pediatric age groups. An appropriate PK study could involve administering either a single dose in “naïve” subjects who have not been receiving regular IGIV replacement therapy, or multiple doses of the test IGIV over a time period of 3 to 5 terminal elimination half-lives, with PK sampling following the last dose. The sample size should consist of 6 to 12 subjects in a given pediatric age group. Two methods can be used for the estimation of PK parameters: • The standard 2-stage PK approach (model-independent and/or modeldependent approach) (Refs. 6 through 8) The standard 2-stage PK approach is the usual approach for the estimation of PK parameters. In this approach, frequent blood sampling is required. Blood samples should be collected over specified intervals depending on the elimination half-life of the drug. It is important in this approach to include enough subjects (e.g., 6 to 12) to give a reasonable estimate of variability.Contains Nonbinding Recommendations• The population PK approach (Refs. 9 and 10) An alternate approach in many pediatric situations is the population PK approach. This approach involves sparse blood sampling from a larger population than would be used in a standard PK study to estimate PK parameters. The population PK approach is more practical in pediatric populations (especially neonates and very young children) than the 2-stage PK approach because it allows for infrequent sampling, sometimes as few as 2 to 4 samples per subject. Because a relatively large number of subjects is studied, estimates of both population means and individual values (POSTHOC Bayesian)5 , as well as estimates of intra- and inter-subject variability can be obtained if the population PK study is properly designed (Refs. 11 through 13). More details for conducting PK studies in pediatric populations can be found in the FDA guidance entitled, “General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products” .