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Pharmacokinetics of Anorectal Nifedipine and Lidocaine (Lignocaine) Ointment following Haemorrhoidectomy

An Open-Label, Single-Dose, Phase IV Clinical Study

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Abstract

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 (Cmax) 245.1±370.8 ng/mL, 73.6 ng/mL; time to reach Cmax (tmax) 69.2±78.3 minutes, 40 minutes; area under the serum concentration-time curve from 0 to 6 hours (AUC6) 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.

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Acknowledgements

Bracco SpA, Milan, Italy, provided financial support for this phase IV clinical study subject to Good Clinical Practice rules, Italian laws and local ethics committee decisions. This financial support was limited to payment of health insurance policies for patients who participated in the trial, supplying investigational products and paying institutions for the costs of material used for every patient.

Pasquale Perrotti and Carmine Antropoli are general staff and colorectal surgeons at ‘A. Cardarelli’ Hospital, Naples, Italy. They wrote this article, are independent of any financial arrangement with the pharmaceutical company whose product was tested in this study, and have no conflicts of interest that are directly relevant to the content of this study. Guglielmo Giannotti carried out surgical procedures and clinical assessments for the evaluation of safety at the Second Department of Surgery, General Hospital of Crema, Crema, Italy, and has no conflicts of interest that are directly relevant to the content of this study. Mario Regazzi and Maria Cusato are the main investigators of a certified centre of Pharmacology — Clinical Pharmacokinetic Laboratory Department of Pharmacology, Foundation IRCCS, San Matteo General Hospital, Pavia, Italy, which carried out the determinations of nifedipine and lidocaine. These investigators have no conflicts of interest that are directly relevant to the content of this study. Enzo Grossi, Patrizia Dominici and Renata Cerutti are employees of/researchers for Bracco SpA. They played a role in planning and application of the methods protocol, coordination of the institutions involved in the study, and the statistical evaluation of data. These roles were limited by Good Clinical Practice rules and Italian laws.

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Authors and Affiliations

  1. Chirurgia Gastroenterologica, Department of Gastroenterology, ‘A. Cardarelli’ Hospital, Via Domenico Fontana, 39, 80128, Naples, Italy

    Pasquale Perrotti

  2. Medical Department, Bracco SpA, San Donato Milanese, Milan, Italy

    Patrizia Dominici & Enzo Grossi

  3. Chirurgia Colon Proctologica, Department of Gastroenterology, ‘A. Cardarelli’ Hospital, Naples, Italy

    Carmine Antropoli

  4. 2nd Department of Surgery, General Hospital of Crema, Crema, Italy

    Guglielmo Giannotti

  5. Clinical Pharmacokinetics Laboratory, Department of Pharmacology, Foundation IRCCS San Matteo General Hospital, Pavia, Italy

    Maria Cusato & Mario Regazzi

  6. Biometric Unit, Bracco SpA, San Donato Milanese, Milan, Italy

    Renata Cerutti

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  1. Pasquale Perrotti
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Correspondence to Pasquale Perrotti.

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Perrotti, P., Dominici, P., Grossi, E. et al. Pharmacokinetics of Anorectal Nifedipine and Lidocaine (Lignocaine) Ointment following Haemorrhoidectomy. Clin. Drug Investig. 29, 243–256 (2009). https://doi.org/10.2165/00044011-200929040-00003

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