TABLE 4.
The results of drug combinations based on IM in GISTs or CML treatment regimens in the clinic.
| Number | Role | Combinatorial drug | Dosage of IM | Sample and numbers | Major results | AUC | Apparent total plasma clearance | Apparent volume of distribution | Terminal elimination half-life | References |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | CYP inducer | Cyclophosphamide | 400 mg/d | GISTs, n = 17 | No drug-drug pharmacokinetic interactions were observed | The AUC (0–24) of cyclophosphamide and of IM were increased from 33.0 to 34.3 ng h/mL, which did not show any significant difference | — | — | The half-life of IM was increased from 14.1 to 16.4 h, which did not show significant difference | Adenis et al. (2013) |
| 2 | CYP inducer | Rifampicin | 400 mg/d | Healthy people, n = 14 | During concomitant rifampicin administration, the mean imatinib Cmax decreased by 54% | The AUC (0–24) and AUC(0–∞) of IM decreased by 68 and 74%, respectively, during rifampicin treatment | The increase in clearance was 385% (348–426%) during rifampicin treatment | — | The half-life of IM decreased from 16.7 ± 3.1 to 8.8 ± 0.7 h during rifampicin treatment | Bolton et al. (2004) |
| 3 | CYP inducer | Phenytoin | 400 –600 mg/d | CML, n = 1 | Phenytoin could induce inadequate responses due to increased imatinib clearance and low IM trough plasma levels | In this case report, pharmacokinetic parameters were not supplied for IM or phenytoin. IM dose was increased from 400 to 600 mg and plasma trough level was increased to 458 ng/ml | Osorio et al. (2019) | |||
| 4 | CYP inhibitor | Panax ginseng | 400 mg/d | CML, n = 1 | A potential interaction resulting in liver toxicity between P. ginseng and IM. | In this case report, pharmacokinetic parameters were not supplied for IM or P. ginseng; however, the indices, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, albumin, and international normalized ratio, were described | Bilgi et al. (2010) | |||
| 5 | CYP inhibitor | Ketoconazole | 200 mg/d | GISTs, n = 14 | Ketoconazole increased the Cmax, AUC (0–24), and AUC(0–∞) by 26% (p < 0.005), 40% (p < 0.0005), and 40% (p < 0.0005), respectively | The AUC (0–24), and AUC(0–∞) of IM were increased from 9,618 ± 4,191 and 14,228 ± 7,359 to 13,498 ± 5,561 and 19,667 ± 8,932 ng h/ml, respectively, when treated with ketoconazole | The clearance of IM decreased from 16.3 ± 5.5 to 11.6 ± 4.0 L/h, when treated with ketoconazole | The apparent volume of distribution of IM did not show any significant difference, which varied from 472 ± 163 to 318 ± 113 L, when treated with ketoconazole | The half-life of IM did no show significant difference (from 20.5 ± 4.4 to 19.2 ± 4.5 h), when treated with ketoconazole | Dutreix et al. (2004) |
| 6 | P-gp substrate | Cyclosporine A | 400 or 600 mg/d | CML with underwent hematopoietic stem cell transplantation, n = 16 | Based on measured drug concentrations, the cyclosporine dosage needed to be reduced, on average, by 27% after initiation of IM (p = 0.004) | The pharmacokinetic parameters were not supplied for IM or cyclosporine a. The authors measured the plasma concentration of cyclosporine a only | Atiq et al. (2016) | |||
| 7 | P-gp agonists | St. John’s wort | 400 mg/d | Healthy people, n = 12 | A 43% increase in clearance and a 30% decrease in the AUC of IM were observed | The AUC (0–24) of IM was decreased by 30%, when treated with st. John’s wort | The clearance of IM decreased from 17.9 to 12.5 L/h, when treated with st. John’s wort | — | The half-life of IM decreased from 12.8 to 9.0 h, when treated with st. John’s wort | Frye et al. (2004) |
| 8 | Cytokine | Interleukin-2 | 400 mg/d | GISTs, n = 21 | IL-2 increased the maximum concentration of IM and its main metabolite NDI; IM did not modulate IL-2 pharmacokinetics | The AUC (0–24) and AUC(0–∞) of IM were increased from 39.6 ± 13.4 and 64.1 ± 28.2 to 64 ± 16.5 and 94.6 ± 30.6 μg h/mL, respectively, when treated with interleukin-2 | The clearance of IM decreased from 7.8 ± 4.9 to 4.7 ± 1.7 L/h, when treated with interleukin-2 | The apparent volume of distribution of IM decreased from 126.5 ± 64.2 to 82.9 ± 24.5 L, when treated with interleukin-2. | The half-life of IM did not show significant difference (from 13.1 ± 8.9 to 13 ± 3.9 h), when treated with interleukin-2 | Pautier et al. (2013) |
| 9 | Cyclin-dependent kinase inhibitor | Flavopiridol | 400 mg/d | CML, n = 21 (17 patients had pharmacokinetic data for IM.) | The combination of flavopiridol and IM is tolerable and produces encouraging responses | AUC values of IM were on average 21% lower in the presence of flavopiridol (p = 0.022) vs. IM’s metabolite, NDI (p = 0.84) | In comparing concentrations immediately prior to and at the end of the 1 h administration of flavopiridol, flavopiridol increased the concentrations of NDI (p = 0.007) but did not affect IM plasma concentrations (p = 0.44). Although the changes in NDI concentrations were statistically significant, the magnitude of these effects was considered to be small | Bose et al. (2012) | ||
| 10 | CYP substrate | Gefitinib | 400 mg/d | CML with lung cancer, n = 1 | Liver function and pancreatic enzyme values gradually worsened after initiation of IM, and the patient was diagnosed with acute pancreatitis. IM was discontinued owing to pancreatic toxicity after 22 days. Lastly, the patient was readmitted with significant deterioration of her clinical situation and died 6 days later | There were no IM or gefitinib plasma concentration data in this case report, only potential discussion from the authors. The interaction most likely arose because imatinib is a CYP2D6 inhibitor and could therefore impair the metabolism of gefitinib (a CYP2D6 substrate) and increase its serum concentration as in the authors analysis | (Escudero-Vilaplana et al. (2020) | |||
| 11 | CYP substrate | Sertraline | 400 mg/d | CML, n = 1 | Final diagnosis was subfulminant toxic acute hepatitis secondary to IM and sertraline treatment | The Naranjo nomogram showed a probable correlation between this adverse effect and the interaction between IM and sertraline. This interaction is extremely rare and the mechanism of action is not clear | Strawn et al. (2019) | |||
CML, chronic myeloid leukemia; IM, imatinib mesylate; GISTs, gastrointestinal stromal tumors; AUC0–24 = area under the serum concentration-time curve from time zero extrapolated to 24 h; AUC0–∞ = area under the serum concentration-time curve from time zero extrapolated to infinity.