Parviz Ghahramani (1), Tatiana Khariton (1), Antonia Periclou (1)
(1) Forest Research Institute, Jersey City, NJ, USA
Objectives: To develop population PKPD models describing the relationship between milnacipran (MLN) and ambulatory blood pressure (BP) and heart rate (HR).
Methods: A double-blind, placebo-controlled study assessed the effects of MLN on ambulatory BP and HR in fibromyalgia (FM) patients, normotensive or with stable hypertension, measured at baseline, Week 4 (steady state for 100 mg/d), and Week 7 (steady state for 200 mg/d). The population PK model [1] was updated and used to predict exposures at time points matching BP or HR readings. The relationships between diastolic (DBP), systolic BP (SBP) or HR and the predicted exposures were assessed using a nonlinear mixed-effects (NLME) modeling in NONMEM. Models for SBP, DBP, and HR were fit separately and consisted of 4 sequentially fitted additive terms: baseline, placebo, drug effect, and residual error. Demographics, hypertensive status, and diurnal variation (using Fourier approach) were evaluated.
Results: The PD population included 49,792 observations from 269 patients. Piece-wise linear relationships between exposure and SBP, DBP, or HR described the data best. Additive inter-individual variability terms were estimated on baseline, placebo and drug effects. No evidence of hysteresis was found. PKPD models suggest that the drug effect on SBP, DBP and HR was near plateau by Week 4. Although the dose and exposure at Week 7 (200 mg/d) was twice those at Week 4 (100 mg/d), the increase in the estimated drug effect was small: the mean increases in DBP, SBP and HR for 100 mg/day were estimated to be 5.0 mmHg, 5.1 mmHg and 12.8 bpm, respectively (Table 1); the additional effects at 200 mg/d dose were not statistically significant compared to 100 mg/day dose. Patients identified as hypertensive had higher estimated SBP and DBP values (but not HR) at baseline; however, the magnitude of increase in DBP and SBP drug effect in hypertensives was not significantly different.
| Table 1 | DBP, mmHg* | SBP, mmHg* | HR, bpm* |
| Drug effect for 100 mg/d | 5.0 (3.8, 6.2) | 5.1 (3.5, 6.7) | 12.8 (11.3, 14.3) |
| Additional drug effect for 200 mg/d | 0.7 (-0.4, 1.8) | 1.2 (-0.5, 3.0) | 1.2 (-0.2, 2.7) |
| *mean (95% CI) | |||
Conclusions: Although exposure to MLN is associated with an increase in SBP, DBP and HR in FM patients, 200 mg/d does not lead to significant additional increases in BP and HR compared to 100 mg/d. Furthermore, hypertensive patients do not appear to have greater increase in BP and HR with increase in MLN exposure as compared to normotensive patients
References:
[1] Population Pharmacokinetic Analysis of Milnacipran in Fibromyalgia Patients and Healthy Volunteers. Parviz Ghahramani, Antonia Periclou. ACOP, 2009
Reference: PAGE 22 () Abstr 2955 [www.page-meeting.org/?abstract=2955]
Poster: Safety (e.g. QT prolongation)