title: The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data.
abstract: OBJECTIVE
  To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication.
  
  
  METHODS
  The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication.
  
  
  RESULTS
  A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups.
  
  
  CONCLUSIONS
  In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.
authors.affiliation: Clinical Pharmacology Unit, University of Pavia, Piazza Botta 10, Pavia, Italy. cinzia.fattore@unipv.it
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fattore
authors.forename: Sara
authors.initials: S
authors.lastname: Messina
authors.forename: Dina
authors.initials: D
authors.lastname: Battino
authors.forename: Danilo
authors.initials: D
authors.lastname: Croci
authors.forename: Daniela
authors.initials: D
authors.lastname: Mamoli
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004790:Enzyme Induction; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid