Comparative study on the bioequivalence of two formulations of pravastatin. Data from a crossover, randomised, open-label bioequivalence study in healthy volunteers.
An open-label, randomised, crossover single-dose study, using two periods, two sequences, with a minimum washout period of 7 days, was conducted in order to assess the comparative bioavailability of a pravastatin (CAS 81131-70-6) 40 mg formulation and that of a reference formulation. Blood samples were collected up to +14 h post dosing, the plasma was separated and pravastatin concentrations were determined by high-performance liquid chromatographic method with tandem mass spectrometry detection (HPLC-MS/MS), with a lower limit of quantification of 0.40 ng/mL. Bioequivalence analyses were conducted using two models. The main analysis was done according to a general linear model (model I) using formulation, period and sequence as fixed model effects, and subject(sequence) and residual as random effects; gender-related differences were investigated using ANOVA (model II), including formulation, period, sequence, gender, sequence-by-gender interaction and gender-by-formulation interaction as fixed model effects and subject within sequence-by-gender interaction and residual as random effect. Mean values of the individual Cmax were 126.73 +/- 61.99 ng/mL and 123.52 +/- 52.78 ng/mL for the test and reference, spectively. Mean +/- SD total area under the curve up to the last measurable concentration (AUClast) was 224.26 +/- 104.74 ng x h/mL for the test formulation and 216.55 +/- 80.30 ng x h/mL for the reference formulation. Mean +/- SD total area under the curve (AUCinf) was 226.72 +/- 104.69 ng x h/mL for the test formulation and 218.81 +/- 79.95 ng x h/mL for the reference. Terminal elimination half-life was 2.15 +/- 0.85 h for test and 1.97 +/- 0.54 h for the reference. Ninety percent confidence intervals were comprised within the bioequivalence acceptance criteria (80-125 %) for all of the parameters analysed, both using model I and model II. Model II returned a statistically significant gender effect (p < 0.05) for Cmax, AUClast and AUCinf but the effect became non-significant (p > 0.05) when the dose was adjusted per body weight for all three parameters. The comparison between male and female mean body weight showed a significant difference: p = 0.03, 95 % confidence intervals 68.27-76.93 kg (men), 56.84-60.61 kg (women). These results suggest that the effect of gender in the bioequivalence analysis in model I could be due to a difference in body weight between males and females. Both formulations were shown to be bioequivalent in terms of rate and extent of absorption, irrespectively of the model used.
Medical Department, Grupo Tecnimede, Prior Velho, Portugal. dmed.ct.tecnimede@mail.telepac.pt
Susana
S
Almeida
Augusto
A
Filipe
Ana
A
Almeida
Ignasi
I
Gich
Rosa
R
Antonijoan
Montserrat
M
Puntes
Manuel
M
Barbanoj
Maria
M
Cruz Caturla
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002138:Calibration; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D017035:Pravastatin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013810:Therapeutic Equivalency
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin