Evaluation of the Pharmacokinetics (PK) and Pharmacodymamics (PD) of Ganciclovir (GCV) in Premature Infants Receiving Treatment for Cytomegalorivus (CMV) Infection

Study Overview
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Brief Summary
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This is a clinical sampling study, and no study drugs will be administered under this protocol. Premature infants who receive intravenous ganciclovir as part of clinical care will be eligible for participation in this study. Intravenous ganciclovir will not be provided under this protocol.

Detailed Description
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This is an open-label, multi-center, clinical sampling study to assess ganciclovir pharmacokinetics and pharmacodynamics in premature infants. Only those subjects who receive ganciclovir for clinical reasons will be enrolled. The decision to initiate ganciclovir therapy will be made by the attending physician based upon his/her clinical decision to treat virologically-confirmed CMV infection; infants receiving such therapy and meeting entry criteria will then be eligible for this study. Therefore, ganciclovir will not provided under this protocol. Subjects meeting enrollment criteria will be entered into this clinical trial. Subjects will be stratified by gestational age and by chronologic age as follows: 1) ≤ 27 weeks 6 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 2) ≤ 27 weeks 6 days gestational age at birth and > 30 days chronologic age at study enrollment; 3) ≥ 28 weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 4) ≥ 28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment. Eight subjects will enroll in each of the four groups, for a total sample size of 32 subjects. Subjects in each cohort with inadequate pharmacokinetic data for analysis (e.g., due to dropping out of the study before PK assessments are performed, or blood sampling obtained but is inadequate for analysis) will be replaced and will not count toward the total of eight subjects in each of the four groups. Additionally, enrollment of an additional 2-3 subjects may be allowed for operational reasons. A full pharmacokinetic profile will be obtained with one of the ganciclovir doses received after enrollment. PK assessments will be obtained after the subject has received study assessment dose 3, 4, 5, 6, 7, or 8 of intravenous ganciclovir. Specimens will be shipped for processing at that time. The pharmacokinetic data will then be provided to the study site, including the area under curve (AUC) and clearance (CL) values for information purposes. Duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. Both whole blood for CMV polymerase chain reaction (PCR) and urine for CMV detection will be obtained once in each study period as long as the subject is receiving intravenous ganciclovir therapy. These specimens will be used to determine blood viral load and ganciclovir resistance. Since ganciclovir is a renally excreted drug, serum creatinine will be drawn for the research protocol on the day that the ganciclovir pharmacokinetic specimens are obtained in order to calculate creatinine clearance using a method such as the modified Schwartz formula, and thus correlate ganciclovir clearance with renal function. Otherwise, data from hematology assessments (WBC count and differential, hemoglobin, platelet count) and from chemistry labs (serum creatinine, aspartate aminotransferase (AST) , and alanine aminotransferase (ALT) will be recorded on the study case report forms during each study period if they are being obtained for clinical reasons, but will not be drawn only for the purposes of the study. Ganciclovir dosing information (mg/dose, dosing interval, and patient weight) will be recorded on the day of the pharmacokinetic blood draws, and weekly from Period 1 through Period 7 as long as the subject is receiving intravenous ganciclovir therapy. If the patient continues to receive intravenous ganciclovir from Study Assessment Day 18 through Study Assessment Day 24 (Period 4), a second PK assessment may be performed at the request of the treating physician if the subject weighs 575 grams or more at the time of specimen collection.

Official Title
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Evaluation of the Pharmacokinetics and Pharmacodynamics of Ganciclovir in Premature Infants Receiving Treatment for Cytomegalovirus Infection

Conditions
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Cytomegalovirus Infections

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from parent(s) or legal guardian(s) Confirmation of CMV infection from urine, blood, or saliva by culture, shell vial, or PCR tests (local lab) Receiving intravenous ganciclovir, prescribed by the patient's physician < 32 weeks gestational age at birth ≥ 500 grams at study enrollment Exclusion Criteria: Imminent demise Current receipt of valganciclovir or foscarnet Receiving breast milk from a mother who is being treated with ganciclovir or valganciclovir Current receipt of other investigational drugs Major congenital anomaly that in the site investigator's opinion may impact drug metabolism or the patient's volume of distribution

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 180 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>≤ 27 weeks 6 days gestational age at birth and ≤ 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. | |
| Group 2<br>≤ 27 weeks 6 days gestational age at birth and > 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. | |
| Group 3<br>≥ 28 weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. | |
| Group 4<br>≥ 28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment. Dose and duration of intravenous ganciclovir therapy is at the discretion of the treating physician and will not be dictated by the research protocol. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics Parameters for Ganciclovir Area Under the Curve at 12 Hours (AUC12mgxh/L) | A series of blood samples will be collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour; required amount of whole blood for plasma ganciclovir determination at each time point is at least 0.2 mL | within 12 hours after dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics Parameters for Ganciclovir, Including Maximum Serum Concentration (Cmax mg/L). | Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour. | within 12 hours after dose administration | 
| Plasma Pharmacokinetics Parameters for Ganciclovir for Half-life (T1/2 hr). | Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour. | within 12 hours after dose administration | 
| Plasma Pharmacokinetics Parameters for Ganciclovir for Clearance (Cl L/hr/kg). | Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour. | within 12 hours after dose administration | 
| Plasma Pharmacokinetics Parameters for Ganciclovir for Volume of Distribution (Vd L). | Looking at the Pharmacokinetics (PK) parameters for Ganciclovir (GCV). A series of blood samples was collected to assess the ganciclovir levels in the blood at the following time points: 0 hour (immediately prior to intravenous (IV) ganciclovir dose; within 15 min prior to dose), 1 hour (immediately after the end of the IV ganciclovir dose; within 15 min after dose), 2-3 hour, 5-7 hour, and 10-12 hour. | within 12 hours after dose administration | 
| Correlation of Ganciclovir Plasma Pharmacokinetics (Clearance (CL) With Whole Blood Cytomegalovirus (CMV) Viral Load. | Comparing the GCV PK clearance (CL L/hr/kg) results to the whole blood CMV viral load data. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Concentration (Cmax) With Whole Blood Cytomegalovirus (CMV) Viral Load. | Comparing the GCV PK results maximum serum concentration (Cmax) to the CMV viral load data. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Area Under the Curve (AUC12) With Whole Blood Cytomegalovirus (CMV) Viral Load. | Comparing the GCV PK results area under the curve (AUC12-mgxh/L) to the whole blood CMV viral load data. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Half-life (T1/2) With Whole Blood Cytomegalovirus (CMV) Viral Load. | Comparing the GCV PK results half-life (T1/2 hr) to the whole blood CMV viral load data. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Volume of Distribution (Vd) With Whole Blood Cytomegalovirus (CMV) Viral Load. | Comparing the GCV PK results volume of distribution (Vd L) to the whole blood CMV viral load data. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Clearance (Cl) With Clearance of CMV in Urine | Comparing the GCV PK results clearance (Cl L/hr/kg) to the clearance of CMV in the urine samples | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Concentration (Cmax) With Clearance of CMV in Urine. | Comparing the GCV PK results to the Cmax with clearance of CMV in the urine samples | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Area Under the Curve (AUC) With Clearance of CMV in Urine. | Comparing the GCV PK AUC results to the clearance of CMV in the urine samples. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Maximum Serum Half Life (T1/2) With Clearance of CMV in Urine. | Comparing the GCV PK half-life results to the clearance of CMV in the urine samples. | 6 weeks | 
| Correlation of Ganciclovir Plasma Pharmacokinetics Volume of Distribution (Vd) With Clearance of CMV in Urine. | Comparing the GCV PK Vd results to the clearance of CMV in the urine samples | 6 weeks |