Safety and Pharmacokinetics of Clindamycin in Pediatric Subjects With BMI ≥ 85th Percentile

Obesity Clinical Trial

— CLIN01  

Official title:

Safety and Pharmacokinetics of Multiple-Dose Intravenous and Oral Clindamycin in Pediatric Subjects With BMI ≥ 85th Percentile (NICHD): CLIN01

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01744730
• Other study ID #: Pro00041855
• Secondary ID: HHSN275201000003
• Status: Completed
• Phase: Phase 1
• First received: December 5, 2012
• Last updated: November 21, 2016
• Start date: June 2013
• Est. completion date: August 2014

Study information

• Verified date: October 2016
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Data and Safety Monitoring BoardUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to better understand how clindamycin works in children who fall in the 85th percentile or higher for body mass index (BMI - a ratio of weight to height). The results of the study will help better understand if children in higher BMI ranges process the medication differently and whether dosing should be adjusted in these children.

Description:

This is a prospective, open-label pharmacokinetic and safety study of multiple doses of IV and oral clindamycin in overweight and obese children ages 2 to 17 years of age. The total study duration is expected to be approximately 24 months; each subject will participate in the study for up to 18 days (screening day; treatment days 1-14 [may be as short as 2 days] followed by an observation period of 3 days post discontinuation of clindamycin therapy or after day 17 (on day 18) of therapy in those who are treated with more than 14 days of clindamycin).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: August 2014
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 17 Years

Eligibility

Inclusion Criteria:

• 2 years - < 18 years of age at the time of first dose of study drug

• Suspected or confirmed infection OR receiving IV clindamycin per routine care

• Negative serum pregnancy test (if female and has reached menarche) within 24 hours of first dose of study drug and agreement to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy test through the last dose of study drug

• BMI = 85th percentile for age and sex, based on Centers for Disease Control (CDC) recommendations

• Signed informed consent/Health Insurance Portability and Accountability Act (HIPAA) documents by the parent/legal guardian and assent (if applicable)

Exclusion Criteria:

• The following apply only to those who are NOT already receiving clindamycin per routine care:

1. History of hypersensitivity or allergic reaction to clindamycin or lincomycin

2. History of C. difficile colitis with previous administration of clindamycin

3. Aspartate aminotransferase (AST) > 120 units/L

4. Alanine aminotransferase (ALT) > 210 units/L

5. Total bilirubin > 3 mg/dL

6. Serum creatinine > 2 mg/dL

7. Receiving a neuromuscular blocker as part of their therapy

• Previous participation in the study

• Subject is on prohibited medication or herbal product (see Appendix II)

• Subject is receiving extracorporeal life support (ECLS)

• Subject is post-cardiac bypass (within 24 hours)

• Subject on inotropes/pressors

• Any other condition or chronic illness that, in the opinion of the principal investigator, makes participation unadvised or unsafe

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Bacterial Infections
• Obesity

Intervention

Drug:
• Clindamycin
Schedule includes 30-40 mg/kg/day dosed every 6 or every 8 hours with a maximum daily dose of 2.7 grams/day. Dosing greater than 2.7g/day will be allowed for children receiving clindamycin as part of clinical care.

Locations

Country	Name	City	State
United States	Akron Children's Hospital	Akron	Ohio
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Children's Mercy Hospital	Kansas City	Kansas
United States	University of Louisville	Louisville	Kentucky

Sponsors (3)

Lead Sponsor	Collaborator
Phillip Brian Smith	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), The EMMES Corporation

Country where clinical trial is conducted

United States, 

References & Publications (27)

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Berezhkovskiy LM. On the accuracy of estimation of basic pharmacokinetic parameters by the traditional noncompartmental equations and the prediction of the steady-state volume of distribution in obese patients based upon data derived from normal subjects. J Pharm Sci. 2011 Jun;100(6):2482-97. doi: 10.1002/jps.22444. — View Citation

Bradley JS, Garonzik SM, Forrest A, Bhavnani SM. Pharmacokinetics, pharmacodynamics, and Monte Carlo simulation: selecting the best antimicrobial dose to treat an infection. Pediatr Infect Dis J. 2010 Nov;29(11):1043-6. doi: 10.1097/INF.0b013e3181f42a53. Review. — View Citation

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del Carmen Carrasco-Portugal M, Luján M, Flores-Murrieta FJ. Evaluation of gender in the oral pharmacokinetics of clindamycin in humans. Biopharm Drug Dispos. 2008 Oct;29(7):427-30. doi: 10.1002/bdd.624. — View Citation

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Gerber JS, Coffin SE, Smathers SA, Zaoutis TE. Trends in the incidence of methicillin-resistant Staphylococcus aureus infection in children's hospitals in the United States. Clin Infect Dis. 2009 Jul 1;49(1):65-71. doi: 10.1086/599348. — View Citation

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Herigon JC, Hersh AL, Gerber JS, Zaoutis TE, Newland JG. Antibiotic management of Staphylococcus aureus infections in US children's hospitals, 1999-2008. Pediatrics. 2010 Jun;125(6):e1294-300. doi: 10.1542/peds.2009-2867. — View Citation

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Koren G, Zarfin Y, Maresky D, Spiro TE, MacLeod SM. Pharmacokinetics of intravenous clindamycin in newborn infants. Pediatr Pharmacol (New York). 1986;5(4):287-92. — View Citation

Leykin Y, Miotto L, Pellis T. Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol. 2011 Mar;25(1):27-36. Review. — View Citation

Morrish GA, Pai MP, Green B. The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol. 2011 Jun;7(6):697-706. doi: 10.1517/17425255.2011.570331. Review. — View Citation

Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. JAMA. 2012 Feb 1;307(5):483-90. doi: 10.1001/jama.2012.40. — View Citation

Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007 Aug;27(8):1081-91. Review. — View Citation

Reed MD. Reversing the myths obstructing the determination of optimal age- and disease-based drug dosing in pediatrics. J Pediatr Pharmacol Ther. 2011 Jan;16(1):4-13. — View Citation

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Weinstein AJ, Gibbs RS, Gallagher M. Placental transfer of clindamycin and gentamicin in term pregnancy. Am J Obstet Gynecol. 1976 Apr 1;124(7):688-91. — View Citation

Weiss M. How does obesity affect residence time dispersion and the shape of drug disposition curves? Thiopental as an example. J Pharmacokinet Pharmacodyn. 2008 Jun;35(3):325-36. doi: 10.1007/s10928-008-9090-8. — View Citation

Wynalda MA, Hutzler JM, Koets MD, Podoll T, Wienkers LC. In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab Dispos. 2003 Jul;31(7):878-87. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics (PK) - Clearance (Cl) in Participants Who Received Multiple Doses of Intravenous (IV) Clindamycin.	In order to understand the impact of obesity on clindamycin PK, PK data were combined to build a PK model from 3 studies that included both obese and non-obese children: 1) PTN_Clinda Obese study (clinicaltrials.gov/ct.gov identifier NCT01744730) n = 21; 2) PTN_POPS study (ct.gov identifier NCT01431326) n = 178; and 3) Staph Trio study (ct.gov identifier NCT01728363) n = 21. The data from the Staph-Trio study were only included for PK modeling and not intended to be compared in the analysis.; PK sampling schedule for PTN_Clinda Obese was: Pre-dose 0 (within 15 minutes prior to IV clindamycin dose), 0.5 (± 5 minutes) after dose was administered, 1-1.5 hours (hrs) after dose, 3-4 hrs after, 5-6 hrs after, and pre-next dose. Samples were collected on multiple days and averaged to arrive at a single value. Comparison of empirical Bayesian Estimates (EBE) for clearance by age cohort are presented below.; Sampling schedule details for PTN_POPS and Staph Trio were comparable.	After first study dose of IV Clindamycin through Day 14 (minimum of 3 samples; maximum of 6).	No
Primary	Pharmacokinetics (PK) - Clearance (Cl) in Participants Who Received Multiple Doses of Intravenous (IV) Clindamycin.	In order to understand the impact of obesity on clindamycin PK, PK data were combined to build a PK model from 3 studies that included both obese and non-obese children: 1) PTN_Clinda Obese study (clinicaltrials.gov/ct.gov identifier NCT01744730) n = 21; 2) PTN_POPS study (ct.gov identifier NCT01431326) n = 178; and 3) Staph Trio study (ct.gov identifier NCT01728363) n = 21. The data from the Staph-Trio study were only included for PK modeling and not intended to be compared in the analysis.; PK sampling schedule for PTN_Clinda Obese was: Pre-dose 0 (within 15 minutes prior to IV clindamycin dose), 0.5 (± 5 minutes) after dose was administered, 1-1.5 hours (hrs) after dose, 3-4 hrs after, 5-6 hrs after, and pre-next dose. Samples were collected on multiple days and averaged to arrive at a single value. Comparison of EBE for clearance by age cohort normalized to 1 kg of body weight are presented below.; Sampling schedule details for PTN_POPS and Staph Trio were comparable.	After first study dose of IV Clindamycin through Day 14 (minimum of 3 samples; maximum of 6 samples).	No
Primary	Pharmacokinetics (PK) - Clearance (Cl) in Participants Who Received Multiple Doses of Intravenous (IV) Clindamycin.	In order to understand the impact of obesity on clindamycin PK, PK data were combined to build a PK model from 3 studies that included both obese and non-obese children: 1) PTN_Clinda Obese study (clinicaltrials.gov/ct.gov identifier NCT01744730) n = 21; 2) PTN_POPS study (ct.gov identifier NCT01431326) n = 178; and 3) Staph Trio study (ct.gov identifier NCT01728363) n = 21. The data from the Staph-Trio study were only included for PK modeling and not intended to be compared in the analysis.; PK sampling schedule for PTN_Clinda Obese was: Pre-dose 0 (within 15 minutes prior to IV clindamycin dose), 0.5 (± 5 minutes) after dose was administered, 1-1.5 hours (hrs) after dose, 3-4 hrs after, 5-6 hrs after, and pre-next dose. Samples were collected on multiple days and averaged to arrive at a single value. Comparison of EBE for clearance by age cohort normalized to 70 kg of body weight are presented below.; Sampling schedule details for PTN_POPS and Staph Trio were comparable.	After first study dose of IV Clindamycin through Day 14 (minimum of 3 samples; maximum of 6 samples).	No
Primary	PK - Volume of Distribution (V) in Participants Who Received Multiple Doses of Intravenous (IV) Clindamycin.	In order to understand the impact of obesity on clindamycin PK, PK data were combined to build a PK model from 3 studies that included both obese and non-obese children: 1) PTN_Clinda Obese study (clinicaltrials.gov/ct.gov identifier NCT01744730) n = 21; 2) PTN_POPS study (ct.gov identifier NCT01431326) n = 178; and 3) Staph Trio study (ct.gov identifier NCT01728363) n = 21. The data from the Staph-Trio study were only included for PK modeling and not intended to be compared in the analysis.; PK sampling schedule for PTN_Clinda Obese was: Pre-dose 0 (within 15 minutes prior to IV clindamycin dose), 0.5 (± 5 minutes) after dose was administered, 1-1.5 hours (hrs) after dose, 3-4 hrs after, 5-6 hrs after, and pre-next dose. Samples were collected on multiple days and averaged to arrive at a single value. Comparison of EBE for volume of distribution by age cohort are presented below.; Sampling schedule details for PTN_POPS and Staph Trio were comparable.	After first study dose of IV Clindamycin through Day 14 (minimum of 3 samples; maximum of 6 samples).	No
Primary	PK - Volume of Distribution (V) in Participants Who Received Multiple Doses of Intravenous (IV) Clindamycin.	In order to understand the impact of obesity on clindamycin PK, PK data were combined to build a PK model from 3 studies that included both obese & non-obese children: 1) PTN_Clinda Obese study (clinicaltrials.gov/ct.gov identifier NCT01744730) n = 21; 2) PTN_POPS study (ct.gov identifier NCT01431326) n = 178; and 3) Staph Trio study (ct.gov identifier NCT01728363) n = 21. The data from the Staph-Trio study were only included for PK modeling and not intended to be compared in the analysis.; PK sampling schedule for PTN_Clinda Obese was: Pre-dose 0 (within 15 minutes prior to IV clindamycin dose), 0.5 (± 5 minutes) after dose was administered, 1-1.5 hours (hrs) after dose, 3-4 hrs after, 5-6 hrs after, and pre-next dose. Samples were collected on multiple days and averaged to arrive at a single value. Comparison of EBE for volume of distribution by age cohort normalized to 1kg of body weight are presented below.; Sampling schedule details for PTN_POPS & Staph Trio were comparable.	After first study dose of IV Clindamycin through Day 14 (minimum of 3 samples; maximum of 6 samples).	No

External Links

•   Clindamycin Injection (Package Insert). Schaumberg, IL: APP Pharmaceuticals; 2008
•   National Institute for Child Health and Human Development
•   Pediatric Trials Network