A Phase I Adaptive, Multiple Dose Pharmacokinetic and Safety Assessment of Valacyclovir in Infants at Risk of Acquiring Neonatal Herpes Simplex Virus Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 23
- 主要终点
- Neonatal plasma acyclovir mean AUC12 concentrations
研究概览
简要总结
A Phase 1 study that will determine the valacyclovir dose that results in a systemic acyclovir exposure comparable to 10 mg/kg of parenterally administered acyclovir, which is an AUC0-12 of 24,000 ngxhr/mL to 48,000 ngxhr/mL. Neonates at risk of acquiring neonatal HSV will be enrolled in one of 2 cohorts. Cohort 1 will be comprised of eight subjects who will receive an initial dose of 10ml/kg of oral valacyclovir. Samples for PK assessments will be obtained to assess the exposure concentration. If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. The dose that these subjects will receive will be predicated upon the pharmacokinetic data from Cohort 1.
详细描述
A Phase 1, open label multicenter trial to assess the safety and pharmacokinetics (PKs) of oral valacyclovir in neonates who are at risk of acquiring neonatal herpes simplex virus disease. This study will determine the valacyclovir dose that results in a systemic acyclovir exposure comparable to 10 mg/kg of parenterally administered acyclovir, which is an AUC0-12 of 24,000 ngxhr/mL to 48,000 ngxhr/mL. Neonates whose mothers have a history of genital HSV infection and received oral valacyclovir in the last several weeks of pregnancy, as per the recommendations of the American College of Obstetrics and Gynecology (ACOG) (9), will be eligible for enrollment. Cohort 1 will be comprised of eight subjects. Following informed consent, each subject will receive 10 mg/kg of oral valacyclovir, and may start taking oral valacyclovir while still in the birth hospital, with subsequent dosing at home, or may start taking oral valacyclovir following discharge from the birth hospital. If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. The dose that these subjects will receive will be predicated upon the pharmacokinetic data from Cohort 1. The primary study objective is to establish the dose of valacyclovir in neonates that reliably achieves systemic acyclovir exposures comparable to 10 mg/kg of parenterally administered acyclovir. The secondary study objectives are: 1) to define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir and 2) to assess and describe the safety profile of valacyclovir among treated neonates.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 1 Day 至 2 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Signed informed consent from parent(s) or legal guardian(s)
- •2. Maternal history of genital HSV infection
- •3. Maternal receipt of oral acyclovir, valacyclovir, or famciclovir suppressive therapy for \>/= 7 days prior to delivery
- •4. Gestational age \>/= 38 weeks at birth
- •5. \/= 2,000 grams
- •* For purposes of this study, the calendar day of birth is Day of Life 0
排除标准
- •Evidence of neonatal HSV infection
- •Evidence of sepsis
- •Known renal anomalies or dysfunction
- •Maternal genital lesions suspicious for HSV at the time of delivery
- •Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry)
- •Current receipt in the neonate of acyclovir, ganciclovir, famciclovir, or any investigational drugs
研究组 & 干预措施
Cohort 1
A cohort of neonates who are at risk of acquiring neonatal herpes simplex virus disease will receive 10 mg/kg of valacyclovir will be administered orally two times daily for 5 days. N=8
干预措施: Valacyclovir (Drug)
Cohort 2
If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. If the mean of observed acyclovir exposures of subjects in Cohort 1 are below 24,000 ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose of 20 mg/kg administered two times daily for 5 days. Alternatively, if the mean of observed acyclovir exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose that has been linearly adjusted downward to target 36,000 ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours (AUC12).
干预措施: Valacyclovir (Drug)
结局指标
主要结局
Neonatal plasma acyclovir mean AUC12 concentrations
时间窗: Days 1 - 5
To establish the dose of valacyclovir in neonates that reliably achieves systemic acyclovir exposures comparable to 10 mg/kg of parenterally administered acyclovir. Acyclovir target concentration of following oral valacyclovir dosing is 24,000 ngxhr/mL to 48,000 ngxhr/mL.
Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC12) of Acyclovir in Plasma
时间窗: 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses
Pharmacokinetics (PK) parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. As blood was only collected up to 8-10 hours post dose, log-linear interpolation was used to calculate the AUC12.
次要结局
- Half-life (t1/2) of acyclovir(Days 1 - 5)
- Occurrence of Grade 3 Adverse Events (AEs)(Days 1 - 42)
- Maximum Serum Concentration (Cmax) of acyclovir(Days 1 - 5)
- Occurrence of Grade 4 Adverse Events and Serious Adverse Events(Days 1 - 42)
- Oral Clearance (CL/F) of acyclovir(Days 1 - 5)
- Time to the maximum concentration (Tmax) of acyclovir(Days 1 - 5)
- Volume of distribution (V/F) of acyclovir(Days 1 - 5)
- Apparent Terminal Elimination Half-life (t1/2) of Acyclovir in Plasma(0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses)
- Maximum Concentration (Cmax) of Acyclovir in Plasma(0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses)
- Apparent Oral Clearance (CL/F) of Acyclovir in Plasma(0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses)
- Time to the Maximum Concentration (Tmax) of Acyclovir in Plasma(0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses)
- Apparent Volume of Distribution During Terminal Phase (V/F) of Acyclovir in Plasma(0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses)
- Frequency of Grade 3 Adverse Events (AEs)(Day 1 through Day 42)
- Frequency of Grade 4 AEs(Day 1 through Day 42)