Pharmacokinetics of anorectal nifedipine and lidocaine (lignocaine) ointment following haemorrhoidectomy: an open-label, single-dose, phase IV clinical study.

Objectives: This study aimed to assess whether topical anorectal application of an ointment containing nifedipine (0.3% w/w) and lidocaine (lignocaine) [1.5% w/w] to patients undergoing Milligan-Morgan haemorrhoidectomy achieves pharmacologically relevant serum concentrations of the active ingredients and has any haemodynamic effects or adverse effects.

Methods: A single dose of 3 g of study ointment was circumferentially applied inside the anus to 24 patients (17 males and 7 females) aged 23-71 years (mean +/- SD: 42.9 +/- 4.9 years) during postoperative dressing after Milligan-Morgan haemorrhoidectomy from March 2007 to January 2008. Blood samples for the determination of nifedipine and lidocaine serum concentrations were drawn before surgery and at 20, 40, 60, 90, 120, 240, 360, 480 and 720 minutes after application. Serum concentrations of nifedipine and lidocaine were determined by a high-performance liquid chromatography method in order to calculate pharmacokinetic parameters. Patients' BP, heart rate and ECG readings were monitored during the study.

Results: Chromatographic signals of nifedipine were sporadically observed in only five patients (20.8%), consistent with therapeutically negligible concentrations and insufficient to permit calculation of any pharmacokinetic parameters. The serum concentrations of nifedipine in these five patients ranged from 5.9 to 18.8 ng/mL. Lidocaine concentrations were detectable in all patients. The means +/- SD and medians of pharmacokinetic parameters for lidocaine were as follows: maximum serum concentration (C(max)) 245.1 +/- 370.8 ng/mL, 73.6 ng/mL; time to reach C(max) (t(max)) 69.2 +/- 78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC(6)) 756.5 +/- 1254.1 ng.h/mL, 238.2 ng.h/mL. Only three patients had maximum serum concentrations above 1000 ng/mL (1037.8, 1044.75 and 1364.1 ng/mL). These outlier concentrations were four to five times lower than the threshold of CNS lidocaine toxicity (5000-6000 ng/mL). No serious local or systemic adverse events were observed throughout the study, and no subjects developed arrhythmias or significant ECG changes. Neither BP nor mean heart rate varied significantly after application of a single dose.

Conclusions: This study demonstrates that single-dose topical application of an ointment containing nifedipine (0.3% w/w) and lidocaine (1.5% w/w) to patients undergoing Milligan-Morgan haemorrhoidectomy is safe to use. Following application onto damaged anorectal mucosa, nifedipine and lidocaine are absorbed into the bloodstream in small quantities that do not have any major implications for the safety of the product. Further studies are required to evaluate nifedipine and lidocaine concentrations in serum using a multiple-dose regimen.