A novel method to estimate the absorption rate constant for two-compartment model fitted drugs without intravenous pharmacokinetic data

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (k a ) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the k a values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (k max ). The accuracy of the direct method in k a estimation was determined using the setting parameters (k 12 , k 21 , and k 10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of k a estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the k a values of these drugs were accurately estimated using the direct method based on good correlations between the k a values and other PK parameters that reflected the absorption properties of drugs in vivo (T max , C max , and C max /AUC 0-t ). This novel method can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment.