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Trial record 9 of 234 for:    clindamycin

PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children (PBPK)

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ClinicalTrials.gov Identifier: NCT02475876
Recruitment Status : Active, not recruiting
First Posted : June 19, 2015
Last Update Posted : July 16, 2019
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Michael Cohen-Wolkowiez, Duke University

Brief 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.


Condition or disease Intervention/treatment Phase
Bacterial Infections Drug: Clindamycin Drug: trimethoprim-sulfamethoxazole Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pharmacokinetics of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Using PBPK
Study Start Date : November 2015
Actual Primary Completion Date : August 31, 2018
Estimated Study Completion Date : June 30, 2020


Arm Intervention/treatment
clindamycin
Each subject will be assigned to study drug (clindamycin or TMP-SMX) at the discretion of the treating clinician. The dose and dosing interval of study drug are dictated by this protocol (see interventions).
Drug: Clindamycin

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.
Other Name: Cleocin

trimethoprim-sulfamethoxazole
Each subject will be assigned to study drug (clindamycin or TMP-SMX) at the discretion of the treating clinician. The dose and dosing interval of study drug are dictated by this protocol (see interventions).
Drug: trimethoprim-sulfamethoxazole

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 Name: Bactrim, TMP-SMX




Primary Outcome Measures :
  1. Maximum observed plasma concentration at steady state (Cmaxss) - clindamycin [ Time Frame: PK sampling taken during 3 continuous days of treatment ]
    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

  2. Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - clindamycin [ Time Frame: PK sampling taken during 3 continuous days of treatment ]
    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

  3. Maximum observed plasma concentration at steady state (Cmaxss) - Trimethoprim-Sulfamethoxazole [ Time Frame: PK sampling taken during 3 continuous days of treatment ]
    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.

  4. Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - Trimethoprim-Sulfamethoxazole [ Time Frame: PK sampling taken during 3 continuous days of treatment ]
    We will use the population PBPK models to simulate drug concentration vs. time data for each individual subject using the characteristics and genetic information of the subjects enrolled in the study. We will compare simulated vs. observed plasma concentrations.


Secondary Outcome Measures :
  1. Number of reported AEs and SAEs [ Time Frame: 33 days ]
    Number of AEs and SAEs reported during (3 continuous days) and up to 30 days after study drug administration

  2. Number of Subjects Heterozygous for any CYP3A Family Genotype [ Time Frame: 33 days ]

    Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions:

    CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910

    Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.


  3. Number of Subjects Heterozygous for any CYP2C9 Genotype [ Time Frame: 33 days ]

    Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions:

    CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910

    Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.


  4. Number of Subjects Homozygous for any CYP3A Family Genotype [ Time Frame: 33 days ]

    Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions:

    CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910

    Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.


  5. Number of Subjects Homozygous for any CYP2C9 Genotype [ Time Frame: 33 days ]

    Genetic analysis of the most important single nucleotide polymorphisms (SNPs) in the CYP3A family and CYP2C9 genes will be performed using commercially available Taqman Polymerase Chain Reactions assays for the following gene expressions:

    CYP3A4: rs35599367, rs2246709, rs4646437, rs2740565, rs4253728 CYP3A5: rs776746, rs10264272, rs15524 CYP3A7: rs2687133, rs2257401 CYP2C9: rs1799853, rs1057910

    Subjects will be classified into homozygous and heterozygotes for allelic variants based on the genotyping results.




Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02475876


Locations
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United States, Arkansas
Arkansas Children's Hospital
Little Rock, Arkansas, United States, 72202
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Michigan
University of Michigan C.S. Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
Michael Cohen-Wolkowiez
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Michael Cohen-Wolkowiez, MD Duke Clinical Research Institute

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Responsible Party: Michael Cohen-Wolkowiez, Associate Professor, Duke University
ClinicalTrials.gov Identifier: NCT02475876     History of Changes
Other Study ID Numbers: PRO00057185
1R01HD076676-01A1 ( U.S. NIH Grant/Contract )
First Posted: June 19, 2015    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Clindamycin
Clindamycin palmitate
Clindamycin phosphate
Bacterial Infections
Trimethoprim, Sulfamethoxazole Drug Combination
Trimethoprim
Sulfamethoxazole
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Folic Acid Antagonists
Anti-Dyskinesia Agents
Cytochrome P-450 CYP2C8 Inhibitors
Cytochrome P-450 Enzyme Inhibitors