Pharmacokinetics of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Using PBPK
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 51
- 试验地点
- 3
- 主要终点
- Maximum observed plasma concentration at steady state (Cmaxss) - clindamycin
研究概览
简要总结
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.
详细描述
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:
- Subject demographics including sex, date of birth, race, and ethnicity
- For infants ≤12 months of age: gestational age (GA) and body weight at birth
- Active medical history (from admission note in medical record)
- Concomitant medications
- 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)
- Targeted physical examination, including weight and length/height
- 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.
- 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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 16 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent from parent or guardian and assent from subject when appropriate
- •Require prevention or treatment of confirmed or suspected infection
- •PMA >36 weeks
- •Able to take oral drugs (TMP-SMX)
- •Sufficient IV access for study drug administration (for clindamycin) and PK sample collection (both drugs) -
排除标准
- •History of allergic reactions to study drugs
- •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).
- •Serum creatinine >2 mg/dl within 48 hours prior to enrollment
- •Known ALT >250 U/L or AST >500 U/L on measurement closest to the time of enrollment
- •Known pregnancy
- •Breastfeeding females
- •On extracorporeal membrane oxygenation support at the time of study drug dosing or PK sampling
- •Any condition that, in the judgment of the investigator, precludes participation because it could affect subject safety -
研究组 & 干预措施
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).
干预措施: Clindamycin (Drug)
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).
干预措施: trimethoprim-sulfamethoxazole (Drug)
结局指标
主要结局
Maximum observed plasma concentration at steady state (Cmaxss) - clindamycin
时间窗: 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.
Maximum observed plasma concentration at steady state (Cmaxss) - Trimethoprim-Sulfamethoxazole
时间窗: 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.
Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - Trimethoprim-Sulfamethoxazole
时间窗: 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.
Area under the plasma concentration versus time curve from the start to the end of one dosing interval at steady state (AUCss) - clindamycin
时间窗: 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.
次要结局
- Number of reported AEs and SAEs(33 days)
- Number of Subjects Heterozygous for any CYP3A Family Genotype(33 days)
- Number of Subjects Homozygous for any CYP2C9 Genotype(33 days)
- Number of Subjects Heterozygous for any CYP2C9 Genotype(33 days)
- Number of Subjects Homozygous for any CYP3A Family Genotype(33 days)
研究者
Michael Cohen-Wolkowiez
Associate Professor
Duke University