Rimegepant (tablet, capsule, Nurtec ODT) 75 mg
Figure. Rimegepant 75 mg: plasma concentration versus clinical pain relief and pain freedom.
Plasma concentration (blue line). Model-predicted plasma concentration for a "typical" subject following a single 75 mg oral dose (tablet formulation, fasted), generated from the sponsor's final population pharmacokinetic model (two-compartment disposition with sequential absorption through four transit compartments followed by a separate first-order absorption compartment; parameters from Table 4-6, FDA Clinical Pharmacology Review, NDA 212728). The simulation predicts Cmax ≈ 727 ng/mL at Tmax ≈ 1.25 h, with a near-plateau from roughly 60–90 minutes before declining. This is a model simulation, not observed data. Because the absorption transit-rate constant (ktr) carries substantial interindividual variability (49.2% CV), a single "typical subject" curve declines somewhat faster after 90 minutes than the true population mean concentration profile reported in the same review (Figure 3-12), which remains essentially flat from about 1.5–2.5 hours — a consequence of averaging across many individuals whose absorption is spread out in time.
Pain relief (red/pink bars). Percentage of patients achieving mild-or-no-pain at 15, 30, 45, 60, 90, and 120 minutes after dosing, read approximately off the tablet-formulation Kaplan-Meier time-to-pain-relief curve pooling Studies 301 and 302 (Figure 3-2, FDA Clinical Review). These intermediate time points are descriptive/exploratory; within the pre-specified, multiplicity-controlled secondary-endpoint hierarchy for these pivotal trials, only the 2-hour pain-relief comparison was formally, statistically tested.
Pain freedom, Study 303 (orange bars). Exact percentage of patients pain-free at 2 hours in Study 303 (ODT formulation), the pivotal trial underlying the current U.S. label: 21.2% rimegepant vs. 10.9% placebo (Table 32, FDA Clinical Review; confirmed against the DailyMed package insert).
Pain freedom, CN170003 (purple bars). Analogous 2-hour pain-freedom result from CN170003, an earlier, independent phase 2 dose-ranging study using the capsule formulation at the same nominal 75 mg dose: 31.4% vs. 15.2%, shown here as a replication check rather than pooled with the Study 303 result because of the differing formulation and trial design. The larger apparent effect size in this smaller, earlier trial compared with the larger, pivotal Study 303 is consistent with regression to the mean — a dose that looks best in a dose-ranging trial tends to have its effect size shrink somewhat in an independent confirmatory trial.
Interpretation. The plasma concentration curve rises steeply through the first hour and plateaus close to the time (~90 min) at which the pain-relief bars first show a clear, though formally untested, numeric separation from placebo — consistent with, but not proof of, a concentration-dependent onset of clinical effect. Pain freedom (a stricter, all-or-nothing endpoint) is only reported here at 2 hours; there is no formally analyzed early pain-freedom time point for rimegepant, so whether a partial pain-freedom effect exists at 15–30 minutes, as plausibly suggested by the pain-relief data, cannot currently be assessed. All time-point comparisons besides the pre-specified formal hierarchy (which included the 2-hour endpoints shown here) are exploratory graph-reads and should be interpreted with corresponding caution.
Plasma concentration (blue line). Model-predicted plasma concentration for a "typical" subject following a single 75 mg oral dose (tablet formulation, fasted), generated from the sponsor's final population pharmacokinetic model (two-compartment disposition with sequential absorption through four transit compartments followed by a separate first-order absorption compartment; parameters from Table 4-6, FDA Clinical Pharmacology Review, NDA 212728). The simulation predicts Cmax ≈ 727 ng/mL at Tmax ≈ 1.25 h, with a near-plateau from roughly 60–90 minutes before declining. This is a model simulation, not observed data. Because the absorption transit-rate constant (ktr) carries substantial interindividual variability (49.2% CV), a single "typical subject" curve declines somewhat faster after 90 minutes than the true population mean concentration profile reported in the same review (Figure 3-12), which remains essentially flat from about 1.5–2.5 hours — a consequence of averaging across many individuals whose absorption is spread out in time.
Pain relief (red/pink bars). Percentage of patients achieving mild-or-no-pain at 15, 30, 45, 60, 90, and 120 minutes after dosing, read approximately off the tablet-formulation Kaplan-Meier time-to-pain-relief curve pooling Studies 301 and 302 (Figure 3-2, FDA Clinical Review). These intermediate time points are descriptive/exploratory; within the pre-specified, multiplicity-controlled secondary-endpoint hierarchy for these pivotal trials, only the 2-hour pain-relief comparison was formally, statistically tested.
Pain freedom, Study 303 (orange bars). Exact percentage of patients pain-free at 2 hours in Study 303 (ODT formulation), the pivotal trial underlying the current U.S. label: 21.2% rimegepant vs. 10.9% placebo (Table 32, FDA Clinical Review; confirmed against the DailyMed package insert).
Pain freedom, CN170003 (purple bars). Analogous 2-hour pain-freedom result from CN170003, an earlier, independent phase 2 dose-ranging study using the capsule formulation at the same nominal 75 mg dose: 31.4% vs. 15.2%, shown here as a replication check rather than pooled with the Study 303 result because of the differing formulation and trial design. The larger apparent effect size in this smaller, earlier trial compared with the larger, pivotal Study 303 is consistent with regression to the mean — a dose that looks best in a dose-ranging trial tends to have its effect size shrink somewhat in an independent confirmatory trial.
Interpretation. The plasma concentration curve rises steeply through the first hour and plateaus close to the time (~90 min) at which the pain-relief bars first show a clear, though formally untested, numeric separation from placebo — consistent with, but not proof of, a concentration-dependent onset of clinical effect. Pain freedom (a stricter, all-or-nothing endpoint) is only reported here at 2 hours; there is no formally analyzed early pain-freedom time point for rimegepant, so whether a partial pain-freedom effect exists at 15–30 minutes, as plausibly suggested by the pain-relief data, cannot currently be assessed. All time-point comparisons besides the pre-specified formal hierarchy (which included the 2-hour endpoints shown here) are exploratory graph-reads and should be interpreted with corresponding caution.
Zavagepant 10 mg Intranasal
Figure. Zavegepant 10 mg intranasal: plasma concentration versus clinical pain relief and pain freedom (Study 301).
Plasma concentration (blue line). Model-predicted plasma concentration for a "typical" subject following a single 10 mg intranasal dose, generated from the sponsor's final population pharmacokinetic model (three-compartment disposition with a sequential zero-order/first-order absorption input into a depot compartment, scaled for the intranasal formulation; parameters from Table 4, FDA Clinical Pharmacology Review, NDA 216386). The simulation predicts a Tmax of roughly 30 minutes, consistent with the reported median Tmax (~0.54 h) for this route. This is a model simulation, not observed data, and represents a single typical-subject trajectory rather than a true population mean curve.
Pain relief (red/pink bars). Percentage of patients achieving mild-or-no-pain at 15, 30, 60, and 120 minutes after dosing in Study 301 (FDA Clinical/Medical Review). Unlike the corresponding rimegepant time points, several of these zavegepant pain-relief comparisons were part of the formally, multiplicity-controlled secondary-endpoint hierarchy for Study 301, including the 15- and 30-minute time points — reflecting the faster expected onset for this intranasal formulation.
Pain freedom (orange bars, 2 hours only). Percentage of patients pain-free at 2 hours in Study 301 (Table 19, FDA Clinical Review): 23.6% zavegepant vs. 14.9% placebo. Earlier pain-freedom time points exist only as an unreadable Kaplan-Meier-type figure in the clinical review and are not shown here numerically.
Interpretation. The rapid rise and early (~30 min) peak of the modeled plasma concentration curve is temporally consistent with zavegepant's comparatively early, formally tested separation from placebo on pain relief — a contrast with rimegepant, whose delayed Tmax (~1.25 h) and untested early time points leave its putative early effect unconfirmed. As with rimegepant, no early (15–30 min) pain-freedom comparison is available for zavegepant, so whether the stricter pain-freedom endpoint is also reached earlier with the nasal formulation cannot be assessed from these data.
Plasma concentration (blue line). Model-predicted plasma concentration for a "typical" subject following a single 10 mg intranasal dose, generated from the sponsor's final population pharmacokinetic model (three-compartment disposition with a sequential zero-order/first-order absorption input into a depot compartment, scaled for the intranasal formulation; parameters from Table 4, FDA Clinical Pharmacology Review, NDA 216386). The simulation predicts a Tmax of roughly 30 minutes, consistent with the reported median Tmax (~0.54 h) for this route. This is a model simulation, not observed data, and represents a single typical-subject trajectory rather than a true population mean curve.
Pain relief (red/pink bars). Percentage of patients achieving mild-or-no-pain at 15, 30, 60, and 120 minutes after dosing in Study 301 (FDA Clinical/Medical Review). Unlike the corresponding rimegepant time points, several of these zavegepant pain-relief comparisons were part of the formally, multiplicity-controlled secondary-endpoint hierarchy for Study 301, including the 15- and 30-minute time points — reflecting the faster expected onset for this intranasal formulation.
Pain freedom (orange bars, 2 hours only). Percentage of patients pain-free at 2 hours in Study 301 (Table 19, FDA Clinical Review): 23.6% zavegepant vs. 14.9% placebo. Earlier pain-freedom time points exist only as an unreadable Kaplan-Meier-type figure in the clinical review and are not shown here numerically.
Interpretation. The rapid rise and early (~30 min) peak of the modeled plasma concentration curve is temporally consistent with zavegepant's comparatively early, formally tested separation from placebo on pain relief — a contrast with rimegepant, whose delayed Tmax (~1.25 h) and untested early time points leave its putative early effect unconfirmed. As with rimegepant, no early (15–30 min) pain-freedom comparison is available for zavegepant, so whether the stricter pain-freedom endpoint is also reached earlier with the nasal formulation cannot be assessed from these data.
Figure. Zavegepant 10 mg intranasal, single dose: population pharmacokinetic model simulation.
Model-predicted plasma zavegepant concentration for a "typical" 70 kg subject following a single 10 mg intranasal dose, generated from the sponsor's final population pharmacokinetic model (three-compartment disposition, with sequential zero-order-then-first-order absorption into a depot compartment and a volume-of-distribution scaling factor for the intranasal route; parameters from Table 4, FDA Clinical Pharmacology Review, NDA 216386). Both panels show the same simulated curve. The left panel (linear scale, first 6 hours) shows the rapid rise and peak; the dotted vertical line marks the reported median Tmax of 0.54 h, close to the simulation's own predicted peak. The right panel (log scale, 0–100 hours) extends the same curve out to four days and overlays open circles representing an approximate, low-confidence read-off of the pooled observed median concentration curve from Figure 4 of the same review (a log-scale figure with a compressed early time axis, pooling single- and multiple-dose data from several studies) — shown only as a rough sanity check on the terminal decline, not as validated ground truth. The simulated curve is not observed data; it represents a single typical-subject trajectory using population-median parameter values, not a true population mean concentration-time profile.
Model-predicted plasma zavegepant concentration for a "typical" 70 kg subject following a single 10 mg intranasal dose, generated from the sponsor's final population pharmacokinetic model (three-compartment disposition, with sequential zero-order-then-first-order absorption into a depot compartment and a volume-of-distribution scaling factor for the intranasal route; parameters from Table 4, FDA Clinical Pharmacology Review, NDA 216386). Both panels show the same simulated curve. The left panel (linear scale, first 6 hours) shows the rapid rise and peak; the dotted vertical line marks the reported median Tmax of 0.54 h, close to the simulation's own predicted peak. The right panel (log scale, 0–100 hours) extends the same curve out to four days and overlays open circles representing an approximate, low-confidence read-off of the pooled observed median concentration curve from Figure 4 of the same review (a log-scale figure with a compressed early time axis, pooling single- and multiple-dose data from several studies) — shown only as a rough sanity check on the terminal decline, not as validated ground truth. The simulated curve is not observed data; it represents a single typical-subject trajectory using population-median parameter values, not a true population mean concentration-time profile.