PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | Any - 16 |
| Updated: | 11/9/2018 |
| Start Date: | November 2015 |
| End Date: | May 30, 2019 |
Pharmacokinetics of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Using PBPK
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.
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.
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.
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.
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 -
We found this trial at
3
sites
Arkansas Children's Hospital Arkansas Children's Hospital (ACH) is the only pediatric medical center in Arkansas...
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225 E Chicago Ave
Chicago, Illinois 60611
Chicago, Illinois 60611
(312) 227-4000
Ann & Robert H. Lurie Children's Hospital of Chicago Ann & Robert H. Lurie Children
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