Is saliva suitable as a biological fluid in relative bioavailability studies? Analysis of its performance in a 4 × 2 replicate crossover design

Abstract

The aim of the present study was to evaluate the suitability of saliva as a biological fluid in relative bioavailability (RBA) studies, with the focus on the statistical design and data variability. A randomized, open-label, four periods and two sequences (4 × 2) crossover RBA study in saliva of two phenytoin (PHT) 100 mg immediate-release capsules was performed. PHT is a narrow therapeutic index drug that has been widely used for epilepsy treatment for many years. Published information regarding its bioavailability is available, but plasma assessed. This study was designed and performed using saliva as the biological fluid and the simplest conditions that produce coherent results with previously published plasma studies. Pharmacokinetic parameters (C (max), T (max), AUC(0-t ), AUC(0-inf), C (max)/AUC(0-t ), K (e), and t (1/2)) for each volunteer at each period were calculated. Four different BE calculations were performed: individual bioequivalence, by the method of moments, and three average bioequivalence with data averaged over the two administrations and with data of periods 1-2 and 3-4. ANOVA calculation showed no significant subject-by-formulation interaction, period and sequence effects. The intra-subject variabilities were at least 20-fold lower than the inter-subject ones for C (max), AUC(0-t ) and AUC(0-inf). In all four BE calculations, the 90% CIs for the T/R ratios of studied pharmacokinetics parameters fell within the 80-125% range proposed by most regulatory agencies.

Saliva versus Plasma Pharmacokinetics: Theory and Application of a Salivary Excretion Classification System

“…On the other hand, phenytoin is highly permeable too but falls into class III since it is highly bound to plasma proteins. 14 For drugs that are excreted in saliva as shown in Table 6, and after accounting for both key parameters by using a multiplicative model (S* = P eff *(fu)), a polynomial relationship with correlation coefficient of 0.99 is obtained between S* and C* dimensionless numbers, as shown in Figure 5. This implies that the higher S*, the higher C*, and hence more drug is available into saliva.…”

“…Fluconazole, erythromycin, carbamazepine and norfloxacin are low protein bound drugs. ,,, They fall into class I since they showed high permeability. On the other hand, phenytoin is highly permeable too but falls into class III since it is highly bound to plasma proteins …”

“…Salivary excretion investigated in this study was for sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin. Paracetamol, phenytoin, carbamazepine, fluconazole, norfloxacin, erythromycin and ibuprofen salivary excretion has been investigated previously. ,− …”

Biopharmaceutical Relevance of Dissolution Profile Comparison: Proposal of a Combined Approach

“…These products were the same assayed in vivo in a relative bioavailability study performed in healthy volunteers (28). Table 9 presents the results of the dissolution profile comparison.…”

“…The two products tested (PHT-F and G) were bioequivalent in vivo even according to the individual bioequivalence methodology applied (28), but their dissolution profiles were only equivalent in terms of their AUC and DE (p > 0.05 ), with f 2 < 50 (Table 9).…”