NAME OF FUNDING SPONSOR: Eunice Kennedy Shriver National Institute of Child Health and Human Development

NAME OF IND SPONSOR: Brian Smith, MD, MPH, MHS, Professor, Department of Pediatrics, Duke Clinical Research Institute

NAME OF STUDY DRUG: Clindamycin

TITLE OF STUDY: Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects with BMI ≥ 85th Percentile (NICHD-2012-CLN01)

PRINCIPAL INVESTIGATOR: Michael Joseph Smith, MD, MSCE, Division of Pediatric Infectious diseases, University of Louisville School of Medicine

PRIMARY AIM

Characterize the PK of multiple-dose IV clindamycin in overweight and obese children and adolescents.

• Secondary Aims

  1. Characterize the PK of multiple-dose oral clindamycin in overweight and obese children and adolescents.
  2. Characterize the safety profile of clindamycin in overweight and obese children and adolescents.

METHODOLOGY: This study was a prospective, open-label safety and PK study of multiple doses of IV and oral clindamycin in overweight and obese children 2 to < 18 years of age. Duration of therapy was up to 14 days for children who receive the first dose of IV clindamycin as the study drug. The total duration of therapy with clindamycin was determined by the treating physician for those children who were receiving clindamycin as part of routine care; however, only 14 days of therapy was considered as study drug period. Study follow-up occurred 3 days (+/− 1 day) after the last dose of study drug. Eligible participants ages 2 to <18 years were identified through the inpatient units at each participating site.

NUMBER OF PARTICIPANTS (PLANNED AND ANALYZED):

Planned: 24

Analyzed: 22 were analyzed for safety and 21 were analyzed for PK

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:

Inclusion Criteria:

1. 2 years – <18 years of age at the time of first dose of study drug
2. Suspected or confirmed infection OR receiving IV clindamycin per routine care
3. Negative serum pregnancy test (if female and has reached menarche) within 24 hours prior to first dose of study drug and agreement to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy test through the last dose of study drug
4. BMI ≥ 85th percentile for age and sex, based on CDC recommendations
5. Obtained informed consent/HIPAA from the parent/legal guardian and assent (if applicable)

Exclusion Criteria:

1. The following apply only to those who are NOT already receiving clindamycin per routine care:

   1. History of hypersensitivity or allergic reaction to clindamycin or lincomycin
   2. History of C. difficile colitis with previous administration of clindamycin
   3. AST > 120 units/L
   4. ALT > 210 units/L
   5. Total bilirubin > 3 mg/dL
   6. Serum creatinine > 2 mg/dL
   7. Receiving a neuromuscular blocker as part of their therapy
2. Previous participation in the study
3. Current exposure to medication listed in Appendix IIA of the protocol (Appendix 16.1.1)
4. Participant is receiving extracorporeal life support (ECLS)
5. Participant is post-cardiac bypass (within 24 hours)
6. Participant on inotropes/pressors
7. Any other condition or chronic illness that, in the opinion of the principal investigator, makes participation unadvised or unsafe

TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION

Clindamycin phosphate, USP (IV) was supplied in vials with clindamycin 150 mg/mL and was diluted prior to IV administration. The concentration of clindamycin in diluent for infusion did not exceed 18 mg/mL. The drug was infused over 30 (+/− 5) minutes. Infusion rates did not exceed 30 mg/minute. The pharmacy prepared the IV formulation.

Clindamycin hydrochloride, USP (PO capsules) was available as 150 mg and 300 mg capsules.

Clindamycin palmitate hydrochloride, USP for oral solution was available in 100 mL bottles and was prepared in the pharmacy at each site based on the reconstitution recommendation in the package insert.

Duration of Treatment: Duration of therapy was up to 14 days for children who receive the first dose of IV clindamycin as the study drug. The total duration of therapy with clindamycin was determined by the treating physician for those children who were receiving clindamycin as part of routine care; however, only 14 days of therapy was considered as study drug period. Study follow-up occurred 3 days (+/− 1 day) after the last dose of study drug.

Dosing: A dose of 30-40 mg/kg/day divided q6h or q8h with a maximum dose of 2.7 g/day was selected based on current labeling. Patients who were receiving clindamycin as part of their routine care were also eligible to participate if their dose could have been adjusted to be at least 30 mg/kg/day upon enrollment. Dosing greater than 2.7 g/day was allowed for children receiving clindamycin as part of clinical care. The dose administered was based on total body weight (WT).

CRITERIA FOR EVALUATION:

Pharmacokinetics: The following primary PK parameters were assessed after multiple IV doses of clindamycin:

1. Clearance (CL)
2. Volume of distribution (V)
3. Area under the curve (AUCτ)

Safety: AEs were collected from the time of consent, throughout the period of study drug administration, and for 3 days following end of therapy with clindamycin. Safety was assessed by frequency and incidence of AEs and SAEs.

STATISTICAL METHODS:

Descriptive statistics, such as number of observations, mean, median, standard deviation, standard error, minimum, and maximum, are presented by cohort for continuous variables (such as age, weight, and BMI). Other descriptive statistics, such as counts, proportions, and/or percentages, are presented by cohort group to summarize discrete variables (such as race and sex). No inferential statistical tests have been performed in this study. All analyses and data summaries were produced using SAS^® Software version 9.2 or higher. A complete Statistical Analysis Plan (SAP) was finalized prior to locking the database for the study. PK samples used to develop the population PK model described in this report were collected from three trials: 1) Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care – NICHD-2011-POP01 (clinicaltrials.gov #NCT01431326; IND# 113,645); 2) Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin Pediatric Subjects with BMI ≥ 85th Percentile – NICHD-2012-CLN01 (Clindamycin Obesity, clinicaltrials.gov #NCT01744730; IND# 115,396); and 3) Pharmacokinetics of Antistaphylococcal Antibiotics in Infants – NICHD-2012-STA01 (Staph Trio, clinicaltrials.gov #NCT01728363; IND# 115,396). PK samples from all studies were analyzed using the same HPLC/MS/MS bioanalytical assay validated according to FDA guidance. The population PK model was developed in the software NONMEM (version 7.2). A forward inclusion-backward elimination approach was used to identify covariates that explain inter-individual variability in clindamycin disposition across age groups. Total body weight (WT), free fat mass (FFM), normal fat mass (NFM), and lean body weight (LBW) were each evaluated as measures to account for differences in body size. Monte Carlo simulations were performed using the final model parameters to assess optimal clindamycin dosing.

RESULTS:

PK Results: A total of 220 subjects contributed 420 PK samples to the analysis; 95 children were overweight or obese (187 PK samples). The final population PK model of the whole study population included WT, postmenstrual age (PMA), albumin (ALB), and α-1 acid glycoprotein (AAG) as statistically significant covariates for CL and V:

For the >6-12 years and >12 years age categories, statistically significant differences between obese and non-obese children were observed in the absolute (i.e., non-weight normalized) V estimates (P<0.001). Terminal elimination half-life was also significantly different, but only for the >6-12 years age group (P=0.01). No other statistically significant differences were observed between obese and non-obese children.

Safety: Overall, clindamycin was very well tolerated in this open-label study. Three AEs (one of which was an SAE) were reported in 2 (9%) of patients, none of which were considered related to study drug.

CONCLUSIONS: After accounting for size-based differences using total body weight and physiologic differences using age, only V and terminal elimination half-life were significantly different between obese and non-obese children. Clindamycin may be dosed based on total body weight (max dose 2.7 g/day) without dose adjustment based solely on obesity.

DATE OF THE REPORT: October 15, 2015