In the last decade, a number of population pharmacokinetic studies were published about many drugs in different populations. Predictability and applicability of these models outside their study settings have not been evaluated. There is a need for evaluating these models using either external data from other published studies or from prospective clinical studies. Such evaluations will lend these models amenable for application in clinical situation that needs precision dosing [16, 30]. All the chosen PopPK models were externally evaluated with our clinical data. In these evaluations, the model reported by Golabchifar et al. [23], Menon et al. [29], and Widmer et al. [27] performed well with the acceptable rMPE (%), rMAPE, and rRMSE values. Using rMPE (%), rMAPE, and rRMSE as a model evaluation metrics will assess both bias and precision [31]. The model proposed by Menon et al. was chosen as the final model for dosing nomogram development because it had the lowest rMPE, rMAPE, and rRMSE. All the other models underpredicted the concentrations, and their evaluation metrics were unsatisfactory for the dosing recommendations, this could be due to the differences in the demographics, biochemical parameters and the ethnicity of the study population. One possible explanation for the better performance of Menon et al.’s PopPK model could be the inclusion of weight as a covariate on CL and Vd. In contrast, Golabchifar et al.’s model included no covariates on the PK parameters, whereas Widmer et al.’s model included age, gender, stage of diagnosis, and weight.The clinical dataset available for external evaluation had 49 patients’ data, but 6 patients were dropped from the study because of unusually high-drug concentrations in those subjects which did not make any pharmacokinetics sense. These concentrations were observed between 9 and 10 h and were three to four times higher than the typical mean concentration of 2.04 µg/mL observed during that time window. Imatinib has a high inter-individual variability in the pharmacokinetic parameters related to the processes of absorption, distribution, metabolism and elimination. This inter-individual variability is purportedly due to factors such as genetic polymorphisms in transporters and metabolizing enzymes, body weight, age, gender, white blood cell (WBCs) count and hemoglobin (Hb) value. Patients with higher body-weight and Hb values reported to have increased CL by 12% and 86% and increase in the Vd by 32% and 60% respectively. If a patient had reduced WBC count by the factor of two, then both CL and Vd increased by 8% and 5% respectively [25]. Takahashi et al. stated that therapeutic drug monitoring along with ABCG2 421 C > A genotyping might be helpful in improved imatinib therapy management as patients with ABCG2 421C/A or A/A genotype were associated with a higher trough concentration than ABCG2 421C/C genotype [14] but when we tried to predict with ABCG2 as a covariate we found no significant impact on the trough concentration among these genotypes. Nevertheless, therapeutic drug monitoring might be important to understand whether the patient’s trough concentrations is above or below the required threshold value (1–1.5 µg/mL).

Several studies have reported that the trough concentration for imatinib is higher in patients with major molecular response (MMR) than in patients without MMR. The same pattern was recognized for complete cytogenetic response (CCyR). The patients had significantly higher MMR (minimum of 3 log reduction in the level of BCR-ABL transcript from a standard baseline after initiation of therapy), when the trough concentration was found to be higher than 1 µg/mL [13,14,15, 33]. There is still a debate on the therapeutic range of imatinib in CML therapy [34]. Main reason attributed to the treatment resistance for imatinib in CML patients was trough concentrations lower than 1 µg/mL [35]. Higher imatinib trough concentrations of 1.5 µg/mL & 3 µg/mL have been reported to be associated with toxicities such as neutropenia, grade 3 myalgia, fluid retention and eyelid edema [5, 9, 10].

In Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial, it has been reported that there is an association between the imatinib Ctrough and the frequency of AEs. Imatinib Ctrough above 1.165 µg/mL had high MMR and CCyR but Ctrough above 3.18 µg/mL has resulted in higher frequency of grade 3 or 4 AEs. However, the upper limit for the therapeutic window have not been reported [36]. Recent studies have suggested that the imatinib Ctrough can be maintained between 1 and 1.5 µg/mL because of higher probability of therapeutic success without drug resistance and lower probability of developing AEs [7, 8, 37]. Based on these reports, we considered the window between 1 and 1.5 µg/mL for proposing dosage regimen for various body-weight ranges.

Pharmacometric simulations using the identified generalizable model for the weight range of 45–120 kg with standard regimen resulted in Ctrough values less than 1 µg/mL in certain weight groups. In certain body-weight groups, trough concentrations were well over 1.5 µg/mL. These simulations showed the need for varied doses in different body-weight groups as opposed to the present fixed dosage regimen to all the body-weight ranges to attain the therapeutic range.

The dosage regimen proposed is based on the simulation for the typical subjects with specific body weight considering variability. The current recommendation remains a broad guideline for initial doses in patients with specific body weights and the doses may have to be adjusted again based on the trough levels of imatinib, if they are outside the desired ranges.

This study has several limitations, including a small number of patients (n = 43) and imatinib plasma samples (n = 145), which may limit the robustness of the results, differences between structural and stochastic PopPK models due to the high BSV in imatinib PK previously described in the literature, and the impact of ethnicity on model performance. The findings of this study also suggest that additional imatinib TDM samples are required when the patient did not show signs of improvement in MMR and CCyR.