title: Quantitative model for the blood pressure-lowering interaction of valsartan and amlodipine.
abstract: The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan.
  
  
  
  PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3.
  
  
  
  A two-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an Imaxmodel with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1+ D2) +ALPHA×(D1× D2). D1and D2are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were -0.171 (95% CI: -0.218, -0.143) for SBP and -0.0312 (95% CI: -0.07739, -0.00283) for DBP. These infra-additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes.
  
  
  
  PKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra-additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified.
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, South Korea.
authors: Young-A
authors: YA
authors: Heo
authors: Department of Pharmacology & Clinical Pharmacology, University of Auckland, New Zealand.
authors: Nick
authors: N
authors: Holford
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, South Korea.
authors: Yukyung
authors: Y
authors: Kim
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, South Korea.
authors: Mijeong
authors: M
authors: Son
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.
authors: Kyungsoo
authors: K
authors: Park
mesh_terms: D017311:Amlodipine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D064368:Healthy Volunteers; D006801:Humans; D008954:Models, Biological; D011237:Predictive Value of Tests; D000068756:Valsartan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D017311:Amlodipine; D000068756:Valsartan
keywords: NONMEM; amlodipine; blood pressure; interaction; valsartan