Population pharmacokinetic modelling and simulation of fremanezumab in healthy subjects and patients with migraine

Abstract

Fremanezumab is a fully humanized IgG 2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability. Methods: Nonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks. Results: A 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658. Conclusions: A comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.

Effect of Fremanezumab Monthly and Quarterly Doses on Efficacy Responses

“…Individual Estimates of Fremanezumab Exposure.-The population PK of fremanezumab were previously characterized using a 2-compartment model with 1st -order absorption and elimination and allometric weight scaling of clearance and volume of the central compartment. 16 Individual-specific measures of fremanezumab exposure were calculated using the individual empirical Bayesian PK parameter estimates obtained from the final population PK model. To illustrate the model behavior for the monthly and quarterly dose regimens upon multiple dosing, Figure 1 illustrates the median (90% prediction interval) simulated fremanezumab concentration-time profiles for the monthly and quarterly dose regimens used in the phase 3 clinical trials over 12 months.…”

“…Given the effect of body weight on fremanezumab PK, 16 the impact of fremanezumab exposure across the range of body weight on the predicted efficacy response was investigated in model-based simulations. The predicted percent of responders (as an average over 3 months) is shown vs body weight quartile and regimen in Figure 6a.…”

“…Fremanezumab Exposure Measures.-For the E-R evaluations, individual-specific measures of fremanezumab exposure following monthly and quarterly dosing were calculated. Using the individual empirical Bayesian PK parameter estimates obtained from the final population PK model, 16 predicted fremanezumab concentration profiles were generated over 28 or 84 days following each monthly or quarterly dose and various exposure measures were calculated. Exposure measures were set to zero for placebo patients.…”

Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials

“…The pharmacokinetic effects are also involved in fremanezumab efficacy. The time to maximum concentration of fremanezumab administered subcutaneously is approximately 5–7 days, and bioavailability was reported at 65.8% 8 . Furthermore, fremanezumab is degraded by enzymatic proteolysis into small peptides and amino acids in the absence of metabolism by liver enzymes, which may prevent drug–drug interactions.…”

“…Moreover, higher doses of humanized monoclonal antibodies have been proposed to saturate cell membrane targets responsible for elimination, causing nonproportional increases in mAb serum concentration 14 . This nonlinear feature of fremanezumab was tested using a two-compartment model with first-order absorption and elimination 8 . However, the effects of this exposure–response relationship on efficacy and safety require further evaluation.…”