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2003
   Verona, Italy

Pregabalin Exposure-Adverse Event Analysis in Patients With Neuropathic Pain, Generalized Anxiety Disorder, or Partial Seizures

Miller R, Kowalski KG, Liu J, Frame B, Burger PJ, Corrigan BW, Bockbrader HN, Lalonde R.

Pfizer Global Research and Development, Ann Arbor, MI 48108, USA.

Objective: To describe the pregabalin exposure-adverse event (dizziness and somnolence) relationship following pregabalin doses in patients with neuropathic pain, generalized anxiety disorder, or partial seizures.

Methods: Patient daily adverse event (AE) scores for the 2 most prevalent AE’s (dizziness and somnolence), were combined from 8 neuropathic pain studies, 3 studies in patients with partial seizures, and 6 studies in patients with generalized anxiety disorder. All studies were randomized, double-blind, multiple dose (TID or BID regimens), placebo-controlled, parallel-group multicenter studies. A mixed-effects proportional odds model was used to characterize the relationship between the probability of an adverse AE score (dizziness and somnolence) using a 4 point ordered categorical scale (none, mild, moderate, severe) and pregabalin exposure in individual patients. Two classes of drug models were considered for both dizziness and somnolence AE’s, Emax-type and linear dose-response.

Results: The dataset consisted of 194,087 observations collected in 4459 subjects. Of these, 63,059 observations were from the placebo group; 6698 were from the 50 mg/day group; 5200 were from the 75 mg/day group; 31,335 were from the 150 mg/day group; 2773 were from the 200 mg/day group; 22,652 were from the 300 mg/day group; 6829 were from the 400 mg/day group; 5386 were from the 450 mg/day group; and 50,155 were from the 600 mg/day group. The percent of adverse event observed over the duration of the trial by pregabalin daily dose is presented in Table 1.

Table 1. % Adverse events observed by pregabalin daily dose.

Dizziness

Somnolence

Daily Dose mg/day

None

Mild

Moderate

Severe

None

Mild

Moderate

Severe

Placebo

97.1

1.9

0.88

0.09

95.7

3.2

0.97

0.07

50

96.6

2.5

0.93

0.00

96.5

0.85

2.66

0.00

75

98.3

1.5

0.13

0.00

97.7

1.88

0.10

0.37

150

94.3

3.9

1.37

0.36

93.1

4.48

2.34

0.10

200

88.3

8.5

3.03

0.14

83.6

13.2

2.74

0.54

300

87.5

9.2

3.13

0.18

88.7

7.4

3.39

0.48

400

84.0

10.4

5.04

0.63

86.6

9.53

3.90

0.00

450

85.6

9.5

4.27

0.61

83.3

9.47

6.47

0.82

600

84.2

9.98

5.18

0.62

85.0

8.71

5.75

0.58

The sigmoid Emax model was considered the best base model to further explore fixed effect relationships. The initial models that describe the severity of dizziness and somnolence using a 4-point ordered categorical response resulted in an extremely bimodal distribution of the empirical Bayes predictions of the ETAs, the ETABAR. A histogram plot demonstrated a primary mode near zero (patients who have no AE’s) and a secondary mode of extremely large values (patients with an AE). The mean ETA’s were significantly different from zero for dizziness (ETABAR = 2.2 [p <0.5 x 10-229]) and somnolence (ETABAR = 2.3 [p <0.16 x 10-189]). These histograms clearly showed that the distribution of ETA’s violated the normality assumption. An attempt to solve this problem was made by applying a 2-stage approach in which separate models were developed for the incidence of AE and for the severity of AE given that an adverse event has occurred. The probability for incidence of dizziness and the conditional probability for severity of dizziness were then used to obtain joint and marginal (unconditional) probabilities for severity of dizziness.

For the incidence model, a sigmoid Emax model adequately describes the dose-response for incidence of dizziness and somnolence. In both cases, the appearance is relatively abrupt with low occurrence of dizziness or somnolence at daily doses less than 150 mg/day. The conditional severity for dizziness and somnolence were well-described by a sigmoid Emax model that took into account a time-dependent exposure effect as well as a time-dependent attenuation of dizziness and somnolence. The rate constant (ke0) of appearance of dizziness with respect to initiation of pregabalin dosing was 1.18 days-1 which corresponds to a half life of appearance of 0.63 days. The rate constant (ke0) of appearance of somnolence with respect to initiation of pregabalin dosing was 0.595 days-1 which corresponds to a half-life of appearance of 1.2 days. These values for onset of AE are consistent with the pregabalin half-life of 6.3 hours and the accumulation of pregabalin plasma concentrations to steady state. The rate constant for attenuation of dizziness was 0.0889 days-1 which corresponds to a half-life of 7.8 days. The rate constant for attenuation of somnolence was 0.101 days-1 which corresponds to a half-life of 6.9 days. These values reflect a decrease in dizziness and somnolence that would reach a new steady state in about 3 to 4 weeks. The results suggest that the probabilities of experiencing dizziness and somnolence during pregabalin treatment increase with pregabalin daily dose. The predicted mean incidence of dizziness or somnolence was at least 2-fold higher at doses >200 mg/day compared to daily doses ≤150 mg/day. Overall, the risk of moderate or severe dizziness or somnolence at any time following pregabalin administration was low (<7% on average). The model predicted risk of moderate or severe dizziness or somnolence increased from <5% on Day 1, peaked at <10% on Day 6, and declined to values of <6% by the end of 4 weeks. To assess the impact of dropouts on this apparent attenuation of AE’s a data set was created in which the last observation carried forward (LOCF) was included for dropouts. The frequency based estimates of the unconditional cumulative probabilities were obtained by averaging the number of observed AE scores ≥m at each time. The time trend observed in the frequency-based probabilities was not as pronounced as the observations for patients without LOCF, however, the tendency in the attenuation was still apparent.

Conclusions: The probability of AE’s increases with dose and is most evident at daily doses of 200 mg/day and greater. The risk of an AE at any time following administration of pregabalin increases to reach a maximum on Day 6 and declines to reach a plateau by the end of 4 weeks.



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