Is Bodyweight-Based Dosing Truly Better Than Flat Dosing for Panitumumab? [Letter]
Jeroen JMA Hendrikx, 1– 3 Jos H Beijnen, 1 Alwin DR Huitema 1– 3
1Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 2Department of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands; 3Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Correspondence: Jeroen JMA Hendrikx
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1006 BE, The Netherlands
Tel +31 205 127 948
Email [email protected]
With great interest we read the paper by Liao et al in which they compared a 2-weekly bodyweight-based (6 mg/kg) and fixed (480 mg) administration of panitumumab, a monoclonal antibody (Mab) binding the EGFR receptor.1 The authors used a population pharmacokinetics model to simulate pharmacokinetics of 1200 virtual individuals for each strategy. The observed interpatient variability in mean simulated AUC (CVAUCmean) was compared and was 34% (fixed dosing) versus 29% (bodyweight- based dosing). Based on this, the authors concluded for panitumumab that “body weight-based approach is the recommended patient dosing strategy”.
View the original paper by Liao and colleagues
A Response to Letter has been published for this article.
With great interest we read the paper by Liao et al in which they compared a 2-weekly bodyweight-based (6 mg/kg) and fixed (480 mg) administration of panitumumab, a monoclonal antibody (Mab) binding the EGFR receptor.1 The authors used a population pharmacokinetics model to simulate pharmacokinetics of 1200 virtual individuals for each strategy. The observed interpatient variability in mean simulated AUC (CVAUCmean) was compared and was 34% (fixed dosing) versus 29% (bodyweight-based dosing). Based on this, the authors concluded for panitumumab that “body weight-based approach is the recommended patient dosing strategy”.
Previously, we assessed feasibility of fixed dosing as an alternative strategy for thirteen Mabs including panitumumab.2 We concluded that fixed dosing is a more rational approach as pharmacodynamics (efficacy and toxicity) of antagonistic Mabs are not concentration-related at concentrations exceeding the minimum target inhibitory concentration (ICmin).2 For panitumumab, the estimated threshold is 3.83 µg/mL.1 The authors compared the CVAUCmean of both dosing strategies.1 However, because of the ICmin, trough levels (Cmin) would be a better parameter for assessing efficacy of panitumumab. Although the observed Cmin after bodyweight-based dosing is reported (Figure 1 and Discussion)1, we miss report of simulated Cmin of the fixed dosing schedule. As the lowest interquartile AUC after fixed and bodyweight-based dosing of panitumumab is comparable (987 versus 908 µg*d/mL, respectively, in Table 2)1, it is likely that Cmin of the both strategies is comparable (~20–30 µg/mL and »ICmin) and, therefore, both strategies have equivalent efficacy.
The reported difference in CVAUCmean for both dosing strategies is mainly caused by the higher exposure of panitumumab in patients with a low bodyweight after fixed dosing (Figure 2)1. This results in a difference between the highest interquartile AUC after fixed and bodyweight-based dosing (1582 versus 1254 µg*d/mL, respectively in Table 2)1. However, this is clinically irrelevant as for panitumumab (like most Mabs in oncology), an exposure-toxicity relationship is absent.2,3 Although increased incidence of skin toxicity has been reported with increasing doses, this is related to the EGFR inhibition and reaches a plateau at doses of ≥2.5 mg/kg.3,4 As onset of ≥grade 2 toxicity is related to better survival and is a result of target inhibition, it even may be evaluated as biomarker for efficacy.3 In fact, the manufacturer reports that doses up to 12 mg/kg have been used and that the safety profile was consistent with the recommended dose.4 Since an exposure-toxicity relationship is absent in the tested dose range, the interpatient variability of Mabs is of less concern as long as Cmin stays above ICmin.
In conclusion, both fixed and bodyweight-based dosing give an exposure that is far above ICmin and therefore give similar clinical benefit and risks. Therefore, we argue that for panitumumab – as for most Mabs in oncology – no dosing strategy is to be preferred over the other. If one should be preferred, it should be the fixed dosing strategy for several reasons.2,5 This is in accordance with the recently FDA and EMA approved fixed doses of nivolumab and pembrolizumab.
The authors declare no conflicts of interest in this communication.
1. Liao MZ, Berkhout M, Prenen H, Dutta S, Upreti VV. Dose regimen rationale for panitumumab in cancer patients: to be based on body weight or not. Clinical Pharmacology. 2020;12:109–114.
2. Hendrikx JJMA, Haanen JBAG, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed dosing of monoclonal antibodies in oncology. Oncologist. 2017;22(10):1212–1221. doi:10.1634/theoncologist.2017-0167
3. Ketzer S, Schimmel K, Koopman M, Guchelaar HJ. Clinical pharmacokinetics and pharmacodynamics of the epidermal growth factor receptor inhibitor panitumumab in the treatment of colorectal cancer. Clin Pharmacokinet. 2017;57(4):455–473.
5. Heinhuis KM, Barkman HJ, Beijnen JH, Hendrikx JJMA. A cost analysis study of the implementation of fixed-dosing of monoclonal antibodies in the Netherlands Cancer Institute. Int J Clin Pharm. 2020. doi:10.1007/s11096-020-01131-z
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