PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children

• Status: Completed
• Trial end date: 2020-06-30
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Michael Cohen-Wolkowiez
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Treatments: Clindamycin; Clindamycin palmitate; Clindamycin phosphate; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Criteria

Inclusion Criteria:

1. Informed consent from parent or guardian and assent from subject when appropriate

2. Require prevention or treatment of confirmed or suspected infection

3. PMA >36 weeks

4. Able to take oral drugs (TMP-SMX)

5. Sufficient IV access for study drug administration (for clindamycin) and PK sample collection (both drugs) -

Exclusion Criteria:

1. History of allergic reactions to study drugs

2. Treatment with the following drugs within 24 hours prior to first dose of clindamycin or expected to receive these drugs during the treatment phase with clindamycin:

• CYP3A4 inhibitors (nefazodone, fluconazole, ketoconazole, fluvoxamine, conivaptan, diltiazem, verapamil, aprepitant, ticlopidine, crizotinib, and imatinib), or

• CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital, troglitazone, pioglitazone, and St. John's wort).

3. Serum creatinine >2 mg/dl within 48 hours prior to enrollment

4. Known ALT >250 U/L or AST >500 U/L on measurement closest to the time of enrollment

5. Known pregnancy

6. Breastfeeding females

7. On extracorporeal membrane oxygenation support at the time of study drug dosing or PK sampling

8. Any condition that, in the judgment of the investigator, precludes participation because it could affect subject safety -