Pharmacokinetics and Pharmacodynamics of Clofazimine for Treatment of Cryptosporidiosis

Cindy X. Zhang, Melissa S. Love, Case W. McNamara, Victor Chi, Ashley K. Woods, Sean Joseph, Deborah A. Schaefer, Dana P. Betzer, Michael W. Riggs, Pui Ying Iroh Tam, Wesley C. Van Voorhis, Samuel L.M. Arnold

Research output: Contribution to journalArticlepeer-review


Infection with Cryptosporidium spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both in vitro and in vivo preclinical models of Cryptosporidium infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on Cryptosporidium infection burden or clinical outcomes. To explore whether clofazimine's lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine in vivo concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using Emax and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of Cryptosporidium infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti-Cryptosporidium efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed.

Original languageEnglish (US)
Article numbere01560-21
JournalAntimicrobial Agents and Chemotherapy
Issue number1
StatePublished - Jan 2022
Externally publishedYes


  • Cryptosporidiosis
  • Cryptosporidium
  • Gastrointestinal
  • Gastrointestinal infection
  • Infectious diseases
  • PK/PD
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases


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