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

NCT01744730 | Completed Phase 1 Results DMC

• 2 other identifiers: Pro00041855HHSN275201000003I
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Bacterial Infections; Obesity

Keywords

Bacterial infections; Obesity; pharmacokinetics; clindamycin

Outcome Measures

Primary Outcomes (5)

• 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).

• 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).

• 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).

• 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).

• 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).

Study Arms (4)

Clindamycin IV-ages 2 to 11 Years Old (BMI 85-95th Percentile)

ACTIVE COMPARATOR

Clindamycin IV: Children ages 2 to 11 years old with BMI 85th to 95th percentile. Their schedule of IV Clindamycin administration included 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 was allowed for children receiving clindamycin as part of clinical care.

Drug: Clindamycin

Clindamycin IV-ages 2 to 11 Years Old (BMI Greater Than 95th)

ACTIVE COMPARATOR

Clindamycin IV: Children ages 2 to 11 years old with BMI greater than 95th percentile. Their schedule of IV Clindamycin administration included 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 was allowed for children receiving clindamycin as part of clinical care.

Drug: Clindamycin

Clinidamycin IV-ages 12 to 17 (BMI 85-95th Percentile)

ACTIVE COMPARATOR

Clindamycin IV: Children ages 12 to 17 years old with BMI 85th to 95th percentile. Their schedule of IV Clindamycin administration included 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 was allowed for children receiving clindamycin as part of clinical care.

Drug: Clindamycin

Clindamycin IV-ages 12 to 17 (BMI Greater Than 95th)

ACTIVE COMPARATOR

Clindamycin IV: Children ages 12 to 17 years old with BMI greater than 95th percentile. Their schedule of IV Clindamycin administration included 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 was allowed for children receiving clindamycin as part of clinical care.

Drug: Clindamycin

Interventions

Clindamycin DRUG

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.

Also known as: Clindamycin phosphate (intravenous), Clindamycin hydrochloride (oral capsules), Clindamycin palmitate (oral solution)

Clindamycin IV-ages 12 to 17 (BMI Greater Than 95th); Clindamycin IV-ages 2 to 11 Years Old (BMI 85-95th Percentile); Clindamycin IV-ages 2 to 11 Years Old (BMI Greater Than 95th); Clinidamycin IV-ages 12 to 17 (BMI 85-95th Percentile)

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• The following apply only to those who are NOT already receiving clindamycin per routine care:
• History of hypersensitivity or allergic reaction to clindamycin or lincomycin
• History of C. difficile colitis with previous administration of clindamycin
• Aspartate aminotransferase (AST) \> 120 units/L
• Alanine aminotransferase (ALT) \> 210 units/L
• Total bilirubin \> 3 mg/dL
• Serum creatinine \> 2 mg/dL
• 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

Sponsors & Collaborators

• Phillip Brian Smith: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• The Emmes Company, LLC: collaborator

Study Sites (4)

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Children's Mercy Hospital

Kansas City, Kansas, 64108, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Akron Children's Hospital

Akron, Ohio, 48109, United States

Location

Related Publications (27)

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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. Epub 2010 May 17.

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• 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. Epub 2012 Jan 17.

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• Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc. 1999 Aug;74(8):825-33. doi: 10.4065/74.8.825.

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• Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007 Aug;27(8):1081-91. doi: 10.1592/phco.27.8.1081.

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• Bearden DT, Rodvold KA. Dosage adjustments for antibacterials in obese patients: applying clinical pharmacokinetics. Clin Pharmacokinet. 2000 May;38(5):415-26. doi: 10.2165/00003088-200038050-00003.

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• Bell MJ, Shackelford P, Smith R, Schroeder K. Pharmacokinetics of clindamycin phosphate in the first year of life. J Pediatr. 1984 Sep;105(3):482-6. doi: 10.1016/s0022-3476(84)80033-5.

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• DeHaan RM, Metzler CM, Schellenberg D, Vandenbosch WD. Pharmacokinetic studies of clindamycin phosphate. J Clin Pharmacol. 1973 May-Jun;13(5):190-209. doi: 10.1002/j.1552-4604.1973.tb00208.x. No abstract available.

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• del Carmen Carrasco-Portugal M, Lujan 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.

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• DeHaan RM, Metzler CM, Schellenberg D, VandenBosch WD, Masson EL. Pharmacokinetic studies of clindamycin hydrochloride in humans. Int J Clin Pharmacol. 1972 Jun;6(2):105-19. No abstract available.

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• Townsend RJ, Baker RP. Pharmacokinetic comparison of three clindamycin phosphate dosing schedules. Drug Intell Clin Pharm. 1987 Mar;21(3):279-81. doi: 10.1177/106002808702100310.

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• 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. doi: 10.1124/dmd.31.7.878.

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• Green B, Duffull S. Caution when lean body weight is used as a size descriptor for obese subjects. Clin Pharmacol Ther. 2002 Dec;72(6):743-4. doi: 10.1067/mcp.2002.129306. No abstract available.

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• Erstad BL. Which weight for weight-based dosage regimens in obese patients? Am J Health Syst Pharm. 2002 Nov 1;59(21):2105-10. doi: 10.1093/ajhp/59.21.2105. No abstract available.

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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. Epub 2011 Jan 19.

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• Gonzalez D, Melloni C, Yogev R, Poindexter BB, Mendley SR, Delmore P, Sullivan JE, Autmizguine J, Lewandowski A, Harper B, Watt KM, Lewis KC, Capparelli EV, Benjamin DK Jr, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act - Pediatric Trials Network Administrative Core Committee. Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. Clin Pharmacol Ther. 2014 Oct;96(4):429-37. doi: 10.1038/clpt.2014.134. Epub 2014 Jun 20.

  PMID: 24949994 RESULT

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  PMID: 8517703 RESULT

Related Links

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

MeSH Terms

Conditions

Bacterial Infections; Obesity

Interventions

Clindamycin; clindamycin phosphate; clindamycin palmitate; Solutions

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lincomycin; Lincosamides; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Glycosides; Carbohydrates; Pharmaceutical Preparations

Limitations and Caveats

Data from 3 different studies was included to increase the robustness of the population PK model developed and leverage all available clindamycin PK data.

Results Point of Contact

• Title: Kevin Watt, MD
• Organization: Duke Clinical Research Institute, Duke University School of Medicine

kevin.watt@dm.duke.edu

919-668-8556

Study Officials

• P. Brian Smith, MD, MHS, MPH

  Duke Medical Center/Duke Clinical Research Institute

  PRINCIPAL INVESTIGATOR

• Kevin Watt, MD

  Duke Medical Center/Duke Clinical Research Institute

  PRINCIPAL INVESTIGATOR

• Michael J Smith, MD

  University of Louisville

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: December 5, 2012
• First Posted: December 7, 2012
• Study Start: June 1, 2013
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: November 29, 2016
• Results First Posted: October 19, 2016

Record last verified: 2016-10

Locations

US (4)