Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection

Marc H Weiner, Radojka M. Savic, William R. Mac Kenzie, Diane Wing, Charles A. Peloquin, Melissa Engle, Erin Bliven, Thomas J. Prihoda, Jonathan A Gelfond, Nigel A. Scott, Susan M. Abdel-Rahman, Gregory L. Kearns, William J. Burman, Timothy R. Sterling, M. Elsa Villarino

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentrationtime curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.

Original languageEnglish (US)
Article numberpit077
Pages (from-to)132-145
Number of pages14
JournalJournal of the Pediatric Infectious Diseases Society
Volume3
Issue number2
DOIs
StatePublished - 2014

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rifapentine
Latent Tuberculosis
Isoniazid
Pharmacokinetics
Tablets
Area Under Curve

Keywords

  • Children
  • Pharmacokinetics
  • Rifapentine
  • Treatment
  • Tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pediatrics, Perinatology, and Child Health

Cite this

Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection. / Weiner, Marc H; Savic, Radojka M.; Mac Kenzie, William R.; Wing, Diane; Peloquin, Charles A.; Engle, Melissa; Bliven, Erin; Prihoda, Thomas J.; Gelfond, Jonathan A; Scott, Nigel A.; Abdel-Rahman, Susan M.; Kearns, Gregory L.; Burman, William J.; Sterling, Timothy R.; Villarino, M. Elsa.

In: Journal of the Pediatric Infectious Diseases Society, Vol. 3, No. 2, pit077, 2014, p. 132-145.

Research output: Contribution to journalArticle

Weiner, MH, Savic, RM, Mac Kenzie, WR, Wing, D, Peloquin, CA, Engle, M, Bliven, E, Prihoda, TJ, Gelfond, JA, Scott, NA, Abdel-Rahman, SM, Kearns, GL, Burman, WJ, Sterling, TR & Villarino, ME 2014, 'Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection', Journal of the Pediatric Infectious Diseases Society, vol. 3, no. 2, pit077, pp. 132-145. https://doi.org/10.1093/jpids/pit077
Weiner, Marc H ; Savic, Radojka M. ; Mac Kenzie, William R. ; Wing, Diane ; Peloquin, Charles A. ; Engle, Melissa ; Bliven, Erin ; Prihoda, Thomas J. ; Gelfond, Jonathan A ; Scott, Nigel A. ; Abdel-Rahman, Susan M. ; Kearns, Gregory L. ; Burman, William J. ; Sterling, Timothy R. ; Villarino, M. Elsa. / Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection. In: Journal of the Pediatric Infectious Diseases Society. 2014 ; Vol. 3, No. 2. pp. 132-145.
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abstract = "Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentrationtime curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.",
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AU - Weiner, Marc H

AU - Savic, Radojka M.

AU - Mac Kenzie, William R.

AU - Wing, Diane

AU - Peloquin, Charles A.

AU - Engle, Melissa

AU - Bliven, Erin

AU - Prihoda, Thomas J.

AU - Gelfond, Jonathan A

AU - Scott, Nigel A.

AU - Abdel-Rahman, Susan M.

AU - Kearns, Gregory L.

AU - Burman, William J.

AU - Sterling, Timothy R.

AU - Villarino, M. Elsa

PY - 2014

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N2 - Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentrationtime curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.

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KW - Rifapentine

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KW - Tuberculosis

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