title: Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.
abstract: OBJECTIVE
  Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines.
  
  
  METHODS
  Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution.
  
  
  RESULTS
  Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH).
  
  
  CONCLUSIONS
  The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure.
authors.affiliation: Discovery Sciences, Janssen Pharmaceutica NV, R&D, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: gteuns@its.jnj.com.
authors.forename: Greet B A
authors.initials: GB
authors.lastname: Teuns
authors.affiliation: Biometrics Reporting, Nonclinical Statistics and Computing, Janssen Pharmaceutica NV, R&D, Turnhoutseweg 30, 2340 Beerse, Belgium; University Hasselt, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Geys
authors.affiliation: Discovery Sciences, Janssen Pharmaceutica NV, R&D, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Sonja M A
authors.initials: SM
authors.lastname: Geuens
authors.affiliation: University Hasselt, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: Discovery Sciences, Janssen Pharmaceutica NV, R&D, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Theo F
authors.initials: TF
authors.lastname: Meert
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment / Q000379:methods*; D012646:Self Administration; D019966:Substance-Related Disorders / Q000209:etiology*
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D003913:Dextroamphetamine
keywords: Abuse potential; Conditioned place preference; Drug discrimination; Methylphenidate; Preclinical drug development; Predictivity; Rat; Self-administration; Translational approach; Withdrawal