title: Parametric time-to-onset models were developed to improve causality assessment of adverse drug reactions from antidiabetic drugs.
abstract: OBJECTIVE
  The aim of this study was to investigate whether the time to onset (TTO) of common adverse drug reactions (ADRs) of antidiabetic drugs could be modeled using parametric distributions and whether these TTO distributions were dependent on patient characteristics. Furthermore, information relevant for daily clinical practice was to be obtained.
  
  
  METHODS
  We performed an exploratory TTO modeling study, using a cohort of diabetes mellitus patients. Four parametric distributions (exponential, lognormal, gamma, and Weibull) were compared in terms of their goodness of fit. Covariates that could influence the TTO were investigated. In addition, TTO mean and median values were summarized for use in clinical practice.
  
  
  RESULTS
  Overall, the gamma distribution provided the best goodness of fit, although differences with the Weibull distribution were negligible in some instances. No differences in TTO distributions between different antidiabetic drugs for a given ADR were found. The TTO was influenced by suspected concomitant medication for metformin-associated diarrhea. Mean and median TTO values were similar for different drug-ADR combinations.
  
  
  CONCLUSIONS
  Our study shows that the TTO of common ADRs associated with antidiabetic drugs can be modeled using the gamma or Weibull distribution. Furthermore, clinically relevant information about these ADRs can be obtained.
authors.affiliation: Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH, 's-Hertogenbosch, The Netherlands. Electronic address: j.scholl@lareb.nl.
authors.forename: Joep H G
authors.initials: JH
authors.lastname: Scholl
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, De Boelelaan 1089a, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van de Ven
authors.affiliation: Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH, 's-Hertogenbosch, The Netherlands; Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Eugène P
authors.initials: EP
authors.lastname: van Puijenbroek
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D000368:Aged; D001317:Austria; D015984:Causality; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008432:Mathematical Computing; D008875:Middle Aged; D015233:Models, Statistical; D013997:Time Factors; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents
keywords: ADR; Causality assessment; Latency; Parametric modeling; Pharmacovigilance; Time to onset