PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children
Condition: Bacterial Infections
MeSH terms: Bacterial Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      Developmental changes in physiology during childhood influence drug dosing. Failure to
      account for these changes leads to improper dosing, which is associated with decreased drug
      efficacy and safety in children. Population physiologically-based pharmacokinetic (PBPK)
      modeling offers the opportunity to predict optimal drug dosing based on physiologic
      parameters adjusted for developmental changes.

      PBPK models are mathematical constructs that incorporate physiologic processes with drug
      characteristics and genetic variances to characterize the dose-exposure relationship across
      the age continuum. These models integrate drug-specific (e.g., metabolism, protein binding)
      and systems-specific (e.g., organ size, blood flow) information to predict the effect of
      different factors (e.g., age, genetic variants, disease) on drug exposure. By accounting for
      these factors and using data from clinical trials to confirm the modeling, PBPK models can
      reduce the number of children needed for clinical trials while maximizing dose-based efficacy
      and safety.

      This trial will evaluate a platform to prospectively validate population PBPK models in
      children. The study drugs, clindamycin and Bactrim (aka TMP-SMX), are ideal candidates to
      evaluate population PBPK models in children due to their differing physico-chemical
      properties and elimination pathways. In addition, a trial of clindamycin and TMP-SMX has
      broad clinical applicability, as both drugs are among the most commonly used agents to treat
      gram-positive infections in infants and children.
    

Detailed description: 
      This is a PK and safety study in infants and children requiring prophylaxis of, or treatment
      for confirmed or suspected infection with clindamycin or TMP-SMX. Each subject will be
      involved in the study for up to 33 days (3 days of therapy, 30 days for serious adverse event
      monitoring).

      STUDY PROCEDURES

      Baseline/pre-dose assessment - After the parent or legally authorized representative has
      signed the IRB-approved informed consent form and after it has been determined that the
      subject satisfies all inclusion and no exclusion criteria, the following evaluations will be
      recorded in the CRF:

        1. Subject demographics including sex, date of birth, race, and ethnicity

        2. For infants ≤12 months of age: gestational age (GA) and body weight at birth

        3. Active medical history (from admission note in medical record)

        4. Concomitant medications

        5. For subjects receiving study drugs per standard of care, record the last 6 doses of
           clindamycin or TMP-SMX received prior to study drug administration (date, time, route of
           administration)

        6. Targeted physical examination, including weight and length/height

        7. Laboratory determinations within 48 hours prior to enrollment if performed per local
           standard of care. If serum creatinine was not collected as standard of care, it will be
           collected for this study to confirm eligibility.

        8. Microbiology determinations within 48 hours prior to enrollment if performed per local
           standard of care.

      Treatment assessments/procedures (Day 1-3) - The following assessments will be conducted each
      day while the subject is on study:

        1. Date, time, route, site of administration, dose, and formulation of each study drug dose

        2. Concomitant medications

        3. PK sampling (blood and urine) with date, time, and site of collection

        4. Genetic sampling (once)

        5. Laboratory determinations if performed per standard of care

        6. Microbiologic determinations if performed per standard of care

        7. Serum sample for determination of alpha-1-acid glycoprotein concentration for subjects
           enrolled in the clindamycin arm only. Alpha-1-acid glycoprotein concentration will be
           measured in one of the plasma PK samples. A separate blood sample is not required.

        8. Study drug-related adverse events AEs and SAEs If available, record laboratory
           determinations daily; if several laboratory determinations are available for the same
           day, record test results closest to administration of study drug.

      PK SAMPLING

      Plasma pharmacokinetics sampling scheme.

      Clindamycin: Sample collection windows are relative to the start of the infusion for IV
      clindamycin, except for the first post-infusion sample, which is relative to the end of the
      infusion.

      Three plasma PK samples will be collected around the first dose according to the following
      sampling windows:

        -  0-10 minutes after the end of the first dose

        -  2-4 hours after the start of the first dose

        -  <30 minutes prior to second dose

      Four plasma PK samples will be collected any time after dose 6 according to the following
      sampling windows.

        -  Pre-dose

        -  0-10 minutes

        -  2-4 hours

        -  <30 minutes prior to next scheduled dose

      While treatment with IV clindamycin is necessary for inclusion in the clindamycin arm of the
      study, subjects may transition from IV to oral clindamycin and be eligible for PK sample
      collection during the oral phase.

      TMP-SMX: Sample collection windows are relative to the administration of oral TMP-SMX.

      Three plasma PK samples will be collected around the first dose according to the following
      sampling windows:

        -  1-3 hours after the end of the first dose

        -  6-8 hours after the start of the first dose

        -  <30 minutes prior to second dose

      Four plasma PK samples will be collected any time after dose 6 according to the following
      sampling windows.

        -  Pre-dose

        -  1-3 hours

        -  6-8 hours

        -  <30 minutes prior to next scheduled dose

      Urine PK samples - Urine PK samples are not required for a subject to complete the study. If
      possible, every effort should be made to collect urine PK samples according to the following
      schedule.

      Clindamycin IV: One urine sample will be collected as timed aliquots of all urine excreted
      during one of the following intervals after dose 6:

        -  0-2 hours

        -  2-4 hours

        -  4-8 hours

      TMP-SMX: One urine sample will be collected as timed aliquots of all urine excreted during
      one of the following intervals after dose 6:

        -  0-3 hours

        -  3-6 hours

        -  6-9 hours

        -  9-12 hours

      Opportunistic PK samples - Opportunistic samples of bone, skin, and synovial fluid will also
      be collected if obtained per standard of care.

      Sampling for genotyping - All blood pellets left over after centrifugation of each plasma PK
      samples will be collected and combined into one whole blood pellet sample per subject. This
      combined whole blood pellet will be sent for genetic analysis of single nucleotide
      polymorphisms in the CYP3A family and CYP2C9 genes.

      STATISTICS

      All subjects who receive at least 1 dose of study drug will be included in the
      intention-to-treat (ITT) population used for the safety analysis. All subjects who provide at
      least 1 evaluable PK sample will be included in the PK analysis. Descriptive statistics such
      as number of observations, mean, median, standard deviation, standard error, minimum, and
      maximum will be presented for continuous variables (such as age, weight, etc.). Other
      descriptive statistics such as counts, proportions, and/or percentages will be presented to
      summarize discrete variables (such as race, sex, etc.). All descriptive analyses will be
      presented by appropriate treatment group (ITT or per-protocol) and overall. A detailed
      description of statistical methods and secondary analyses will be prepared and presented in
      the statistical analysis plan prior to data lock for final analyses.
    

Intervention name(s): Clindamycin; trimethoprim-sulfamethoxazole
Intervention type(s): Drug; Drug
Intervention description(s): Route of administration is IV for all Cohorts. Dosing interval is every 8 hrs. for all Cohorts:
Cohort 1; No. Subjects = 5; Age 1-5 months; Dose = 9 mg/kg;
Cohort 2; No. Subjects = 5; Age >5 months to 1 year; Dose =12 mg/kg;
Cohort 3; No. Subjects = 5; Age >1-2 years; Dose =12 mg/kg.
Cohort 4; No. Subjects = 4; Age >2-6 years; Dose =12 mg/kg.
Cohort 5; No. Subjects = 4; Age >6-12 years; Dose =10 mg/kg.
Cohort 6; No. Subjects = 4; Age >12-16 years; Dose =10 mg/kg.; Route of administration is PO for all Cohorts. Dosing interval is every 12 hrs. for all Cohorts:
Cohort 1; No. Subjects = 5; Age 1-5 months; Dose = 6 mg/kg.
Cohort 2; No. Subjects = 5; Age >5 months to 1 year; Dose = 6 mg/kg.
Cohort 3; No. Subjects = 5; Age >1-2 years; Dose = 6 mg/kg.
Cohort 4; No. Subjects = 4; Age >2-6 years; Dose = 6 mg/kg.
Cohort 5; No. Subjects = 4; Age >6-12 years; Dose = 6 mg/kg.
Cohort 6; No. Subjects = 4; Age >12-16 years; Dose = 4 mg/kg.
Other intervention name(s): Cleocin; Bactrim, TMP-SMX
Intervention MeSH terms: Clindamycin; Clindamycin palmitate; Clindamycin phosphate; Trimethoprim, Sulfamethoxazole Drug Combination; Trimethoprim; Sulfamethoxazole
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other