Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis

Mark J. Abzug, Gretchen Cloud, John Bradley, Pablo J. Sánchez, José Romero, Dwight Powell, Martha Lepow, Chitra Mani, Edmund V. Capparelli, Sharon Blount, Fred Lakeman, Richard J. Whitley, David W. Kimberlin

Research output: Contribution to journalArticle

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Abstract

Background. Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. Methods. Infants ≤12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. Results. Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (≤50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally ≤50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. Conclusions. The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalPediatric Infectious Disease Journal
Volume22
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

Enterovirus
Meningitis
Placebos
Polymerase Chain Reaction
Pharmacokinetics
Enterovirus Infections
Pharmaceutical Preparations
Safety
pleconaril
Oropharynx
Rectum
Nervous System
Hospitalization

Keywords

  • Enterovirus
  • Infants
  • Meningitis
  • Pharmacokinetics
  • Pleconaril

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Abzug, M. J., Cloud, G., Bradley, J., Sánchez, P. J., Romero, J., Powell, D., ... Kimberlin, D. W. (2003). Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. Pediatric Infectious Disease Journal, 22(4), 335-340. https://doi.org/10.1097/00006454-200304000-00009

Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. / Abzug, Mark J.; Cloud, Gretchen; Bradley, John; Sánchez, Pablo J.; Romero, José; Powell, Dwight; Lepow, Martha; Mani, Chitra; Capparelli, Edmund V.; Blount, Sharon; Lakeman, Fred; Whitley, Richard J.; Kimberlin, David W.

In: Pediatric Infectious Disease Journal, Vol. 22, No. 4, 01.04.2003, p. 335-340.

Research output: Contribution to journalArticle

Abzug, MJ, Cloud, G, Bradley, J, Sánchez, PJ, Romero, J, Powell, D, Lepow, M, Mani, C, Capparelli, EV, Blount, S, Lakeman, F, Whitley, RJ & Kimberlin, DW 2003, 'Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis', Pediatric Infectious Disease Journal, vol. 22, no. 4, pp. 335-340. https://doi.org/10.1097/00006454-200304000-00009
Abzug, Mark J. ; Cloud, Gretchen ; Bradley, John ; Sánchez, Pablo J. ; Romero, José ; Powell, Dwight ; Lepow, Martha ; Mani, Chitra ; Capparelli, Edmund V. ; Blount, Sharon ; Lakeman, Fred ; Whitley, Richard J. ; Kimberlin, David W. / Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. In: Pediatric Infectious Disease Journal. 2003 ; Vol. 22, No. 4. pp. 335-340.
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abstract = "Background. Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. Methods. Infants ≤12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. Results. Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90{\%} inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (≤50{\%}) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally ≤50{\%}) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. Conclusions. The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.",
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AU - Cloud, Gretchen

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AU - Romero, José

AU - Powell, Dwight

AU - Lepow, Martha

AU - Mani, Chitra

AU - Capparelli, Edmund V.

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AU - Whitley, Richard J.

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N2 - Background. Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. Methods. Infants ≤12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. Results. Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (≤50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally ≤50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. Conclusions. The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

AB - Background. Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. Methods. Infants ≤12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. Results. Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (≤50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally ≤50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. Conclusions. The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

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