Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

Abstract

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

Precision Dosing of Targeted Therapies Is Ready for Prime Time

“…If a dose adjustment is made, the next PK sample could be drawn after 4 weeks for most compounds, so this could again be combined with a regular visit. Although the target exposure is mostly based on a certain trough level (i.e., concentration right before administration of the next dose), it is often sufficient to obtain a single blood sample at a random time point, as trough levels can then be estimated (27,28). From a financial perspective, these expensive drugs should be supplied for one month at a time, so that the ordered amount is completed by the time a potential dose adjustment would be made.…”

A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis

“…Several Cmax concentration datapoints were used to fit the PBPK models: 200 mg dose Cmax, 400 mg dose Cmax ( 67 ), and 400 mg initial dose followed by 200 mg doses until achieving Cmax at the steady state ( 95 ). Additionally, clearance-related datapoints were extrapolated and used to refine the model ( 68 ). The resulting PBPK models adjusted to all reported Cmax values and extrapolated clearance data points with an R 2 > 0.95 ( Figure 3 ).…”

“…The clearance constant parameter ( k el ) was calculated by fitting a general model to pharmacokinetics data points. We used European Medicine Agency’s C max values, and additional points were extrapolated using C max , half-life, and T max parameters ( 67 , 68 ).…”

The Utility of Genomics and Functional Imaging to Predict Sunitinib Pharmacokinetics and Pharmacodynamics: The Predict Su Study

“…[42] TDM approaches have included sampling for C trough , [43] or after the T max with extrapolation to trough levels. [44] Other approaches have included toxicity-adjusted dosing in combination with TDM. [45] In conclusion, the study reported here represents the rst attempt to correlate the combination of end…”