Relevance of the drug-drug interactions between lidocaine and the pharmacokinetic enhancers ritonavir and cobicistat.

With great interest we read the article by Antonio et al.[1] reporting on the serological response to syphilis treatment with penicillin benzathine or doxycycline in patients with HIV following a manufacturing shortfall of penicillin benzathine. No differences in serological response were observed between the two treatment strategies. Long-acting penicillin formulations, however, remain first-line treatment for syphilis [2]. Dependent on the stage of the infection, treatment is recommended by a single injection of 2.4 million units benzylpenicillin benzathine [early infection (acquired within the last 12 months)] or by three successive weekly injections of 2.4 million units (late infection). Administration of benzylpenicillin benzathine is recommended to be split over two doses of 1.2 million units, each in one buttock [3]. Discomfort of these injections can be reduced by replacing part of the solvent by a lidocaine (lignocaine) solution [3]. In addition to manufacturing shortfalls, treatment with benzylpenicillin benzathine may be complicated by drug–drug interactions between lidocaine and components of HIV treatment regimens, especially with inhibitors of lidocaine metabolism.

Lidocaine is metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to its metabolite monoethylglyxinexylidide (MEGX) [4]. To enhance exposure to antiretroviral drugs, such as atazanavir, darunavir and elvitegravir, ritonavir and cobicistat are used as boosters in combined antiretroviral therapy. Ritonavir and cobicistat inhibit CYP3A4, resulting in an increased exposure (increased area under the curve), increased maximum concentration (Cmax) and increased half-life (t1/2) of antiretroviral drugs that are substrates of CYP3A4 [5]. Drug–drug interactions between ritonavir or cobicistat and lidocaine have been suggested to increase lidocaine exposure by more than three-fold [6], complicating treatment with benzylpenicillin benzathine as this interaction may lead to higher plasma lidocaine levels and adverse effects, including neurological and cardiac side effects. Neurological side effects may consist of respiratory depression, convulsion and coma. Cardiac effects may include elevated blood pressure, increased heart rate (HR) and cardiac output with mild intoxications and, with severe intoxications, reduced HR, conduction velocity and contraction of the heart with dilated vessels [7]. The clinical relevance of the interaction between ritonavir and cobicistat and lidocaine during the treatment of syphilis in HIV patients has not been reported thus far.

To determine the relevance of this interaction, lidocaine peak serum levels were determined in three male HIV-positive patients suspect for syphilis infection (refer to Table 1 for details on the patients). Patients were treated with two injections of 1.2 million units benzylpenicillin benzathine dissolved in 2 ml of water for injection and 2 ml of lidocaine 20 mg/ml, according to local guidelines. In total 80 mg of lidocaine was administered by intramuscular injection. Peak concentrations for lidocaine are expected about 30–60 min after intramuscular administration [8]. Lidocaine serum levels were determined with a validated liquid chromatography–tandem mass spectrometry method. Lidocaine peak serum levels were found to range from 0.2 to 0.6 mg/l (Table 1). Therapeutic lidocaine levels for the treatment of arrhythmia are in the range 1.5–6 mg/l [8-10]. Our observations show that the interaction between lidocaine and ritonavir or cobicistat is not of clinical relevance for this specific patient group and lidocaine may be used safely in the treatment of syphilis with benzylpenicillin benzathine. However, if higher doses of lidocaine are administrated, this interaction may become relevant, especially as pharmacokinetic modelling indicates that inhibition of CYP3A4 may result in an increased half-life. In these cases, use of lidocaine should be avoided or lidocaine drug concentrations should be monitored, especially in old patients or patients treated with drugs known to affect hepatic blood flow or metabolism [10].

Table 1

Patient characteristics (concomitant), medication and lidocaine serum concentrations.

Patient number	Age (years)	Weight (kg)	cART	Other medication	T (min)	Peak (lidocaine) (mg/l)
1	52	90.7	Ritonavir 100 mg qdEmtricitabine 200 mg bidTenofovir 245 mg bidDarunavir 800 mg qd	Beclomethasone nasal spray 50 μg qd	31	0.2
2	53	93.5	Cobicistat 150 mg qdElvitegravir 150 mg qdEmtricitabine 200 mg qdTenofoviralafenamide 10 mg qd	Acenocoumarol on basis of INRCalcium carbonate 1.25 g qdCholecalciferol 800 IU qd	56	0.5
3	59	78	Ritonavir 100 mg bidDarunavir 600 mg bidEmtricitabine 200 mg qdTenofovir 245 mg qdEtravirine 200 mg bid	None reported	32	0.6

cART, combination antiretroviral therapy; INR, international normalized ratio; IU, international units; T, time after administration.

Acknowledgements

The study was not financially supported by external funding sources.

Transparency declarations: W.F.W.B. reports reimbursement paid to institution for investigator-initiated study from Janssen-Cilag, financial compensation paid to institution for multicenter study by GSK and catering of a symposium by Janssen-Cilag, all outside the submitted work.

Conflicts of interest

There are no conflicts of interest.