125: Pregabalin-codeine-disease Interactions in Patients With Acute Herpetic or Postherpetic Neuralgia

Statement of Purpose, Innovation or Hypothesis: Understand the implications of neuropathic pain in herpes zoster on pregabalin and codeine interaction to guide suitable dose regimens in the clinical practice considering that a different drug-drug interaction profile may exist in patients with acute herpetic neuralgia (AHN) or postherpetic neuralgia (PHN) compared with healthy participants (HP). Pregabalin pharmacokinetics were assessed in plasma and urine whereas codeine and its active metabolites morphine and morphine-6-glucuronide (M6G) were assessed in plasma.

Description of Methods & Materials: Eligible HP (n=10) and patients diagnosed with AHN (n=7) or PHN (n=7) were recruited in accordance with the ethics committee of the institution. All participants were previously phenotyped as CYP2D6 normal metabolizers (NM) following a single oral dose of metoprolol (10mg) as a probe (log plasma concentrations ratios of metoprolol and its alpha hydroxylated metabolite lower than 1.5). In the morning, under fasted condition, all participants received a single oral dose of pregabalin (75mg) and codeine (30mg) with 250 mL of water. Serial plasma samples and urine were collected until 24h after drug administration. Pregabalin, codeine, morphine and M6G were analysed using validated LC-MS/MS methods and pharmacokinetic parameters were calculated using the Phoenix WinNonlin^TM software employing a noncompartmental analysis. Pharmacokinetic parameters are presented in Table 1 as geometric means (95%CI).

Data & Results: Pregabalin AUC0-inf [20.21 h*µg/mL (17.20-23.74)], Ae [36.97 mg (29.10-46.98)] and Fel [49.30 % (38.80-62.63)] were significantly lower (p < 0.05 Tukey's Honest Significant Difference test) in HP group when compared with the AHN [AUC0-inf 37.00 h*µg/mL (28.91-47.35), Ae 64.29 mg (55.03-75.11) and Fel 85.72 % (73.37-100.14)] and PHN groups [AUC0-inf  29.26 h*µg/mL (22.25-38.50), Ae 68.19 mg (61.76-75.28) and Fel 90.92 % (82.35-100.38)], whereas apparent  clearance [Cl/F  3.93 L/h (3.38-4.56] and apparent distribution volume [Vd/F 30.09 L (25.72-35.20)] were significantly higher in HP group when compared with the AHN group [Cl/F 2.17 L/h (1.66-2.83) and Vd/F 18.09 L (11.49-28.49)]. No differences in pregabalin pharmacokinetic parameters were observed between AHN and PHN groups. Pregabalin apparent clearance (Cl/F) and apparent volume of distribution (Vd/F) were correlated in the log transformed function [(p=0.00005 Pearson's test] when all participants of the study (n=24) were analysed together. Regarding codeine pharmacokinetics, no differences (p >0.05 Tukey's Honest Significant Difference test) were observed in plasma exposure (AUC0-inf) of unchanged drug [193.28 ng.h/mL (114.24-327.01) vs 168.98 (107.52-265.57) vs 202.32 (150.59-271.83)], morphine [19.14 ng.h/mL (11.74-31.20) vs 16.78 (11.95-23.56) vs 20.76 (13.32-32.36)] and M6G [26.52 ng.h/mL (12.34-57.00) vs 39.95 (19.13-83.44) vs 68.39 ng.h/mL (42.02-111.33)] across  AHN, PHN and HV, respectively.

Interpretation, Conclusion or Significance: Acute herpetic neuralgia and postherpetic neuralgia do not alter the plasma exposure of codeine, morphine and M6G. However, the administration of a single oral dose of codeine 30 mg reduces pregabalin bioavailability and, consequently, its plasma exposure in healthy participants, but not in patients with herpetic neuralgia, inferring an example of drug-drug-disease interaction.

Disclosures:

Citations/References: KIRCHHEINER, J. et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The pharmacogenomics Journal. 2007; 7: 257-265. DWIVEDI, J. et al. An Improved LC-ESI-MS/MS Method to quantify pregabalin in human plasma and dry plasma spot for therapeutic monitoring and pharmacokinetic applications. Therapeutic Drug Monitoring. 2018; 40 (5): 610-619. MANDAL, U. et al. Determination of pregabalin in human plasma using LC-MS-MS. Chromatographia. 2008; 67 (3/4): 237-243. SHAH, G. R.; GHOSH, C.; THAKER, B.T. Determination of Pregabalin in human plasma by electrospray ionization tandem mass spectroscopy. Journal of Advanced Pharmaceutical Technology & Research. 2010; 1(3): 354-357.

Additional Information/Authors: Acknowledgement FAPESP and CNPq.