Effect of Tablet Crushing on Drug Exposure in the Treatment of Multidrug-Resistant Tuberculosis

INT J TUBERC LUNG DIS 23(10):1068–1074 Q 2019 The Union http://dx.doi.org/10.5588/ijtld.18.0775 Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis R. Court,1 M. T. Chirehwa,1 L. Wiesner,1 N. de Vries,2 J. Harding,3 T. Gumbo,4 G. Maartens,1 H. McIlleron1 1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, 2Brooklyn Chest Hospital, Cape Town, 3DP Marais Hospital, Cape Town, South Africa; 4Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA SUMMARY SETTING: Treatment outcomes in multidrug-resistant compartmental analysis was used to derive the key tuberculosis (MDR-TB) are poor. Due to drug toxicity pharmacokinetic measurements. and a long treatment duration, approximately half of RESULTS: Twenty participants completed the study: 15 patients are treated successfully. Medication is often were men, and the median age was 31.5 years. There was crushed for patients who have difficulty swallowing a 42% reduction in the area under the curve AUC0–10 of whole tablets. Whether crushing tablets affects drug INH when the tablets were crushed compared with exposure in MDR-TB treatment is not known. whole tablets (geometric mean ratio 58%; 90%CI 47– OBJECTIVE AND DESIGN: We performed a sequential 73). Crushing tablets of pyrazinamide, moxifloxacin, pharmacokinetic study in patients aged .18 years on ethambutol and terizidone did not affect the bioavail- MDR-TB treatment at two hospitals in Cape Town, ability significantly. South Africa. We compared the bioavailability of CONCLUSION: We recommend that crushing of INH pyrazinamide, moxifloxacin, isoniazid (INH), ethambu- tablets in the MDR-TB treatment regimen be avoided. tol and terizidone when the tablets were crushed and Paediatric INH formulations may be a viable alternative mixed with water before administration vs. swallowed if the crushing of INH tablets is indicated. whole. We sampled blood at six time points over 10 h KEY WORDS: MDR-TB; crushed; pharmacokinetic; under each condition separated by 2 weeks. Non- bioequivalence; bioavailability OUTCOMES FOR TREATMENT of multidrug- therefore, require drug administration via a nasogas- resistant tuberculosis (MDR-TB) are poor, with tric tube. treatment completion rates of ~54% being reported.1 However, tablet crushing may alter the bioavail- A heavy pill burden, together with nausea and ability of the active ingredients within the drug.7 vomiting, which has been reported to occur in Studies comparing the bioavailability of crushed vs. 75% of patients,2–4 contribute to poor regimen whole medication have shown that crushing decreas- tolerability.5 es the plasma concentrations of some drugs, including It is standard practice in some centres to crush rifapentine,8 but not of others.9–12 Combining the medication, and mix the crushed tablets with water to crushed tablets of a multidrug regimen is common; ease ingestion in the belief that this will reduce moreover, the tablets may be mixed into a vehicle- gastrointestinal upset. Crushing of tablets before containing substance that reacts with the drugs.12,13 administration is also common in young children Remnants may also adhere to the walls of the because suitable formulations are frequently not container in which the medication was crushed and available for those unable to swallow whole tablets. thereby escape ingestion. Subtherapeutic plasma One qualitative study at a paediatric hospital in Cape concentrations of some first and second-line anti- Town, South Africa, reported that 69% of caregiv- tuberculosis drugs have been associated with poor ers crush, dissolve or mix TB medication with food clinical outcomes, including acquisition of drug before administration.6 Crushing tablets may also be resistance.14–16 It is, therefore, important to under- necessary in critically ill patients with a depressed stand whether tablet crushing affects exposure of the level of consciousness who cannot swallow and, drugs used to treat MDR-TB, many of which are key Correspondence to: Richard Court, Division of Clinical Pharmacology, University of Cape Town, Groote Schuur Hospital, K45 Old Main Building, Observatory 7925, South Africa. e-mail: [email protected] Article submitted 14 November 2018. Final version accepted 2 March 2019. Bioavailability of crushed anti-MDR-TB drugs 1069 drugs in the recently updated World Health Organi- water in a mixing cup. After ingestion, tablet zation (WHO) recommended management guide- remnants adhering to the walls of either the mortar, lines.17 pestle or mixing cup were scraped off with a spatula, mixed with a small unmeasured amount of water, and STUDY POPULATION AND METHODS swallowed by the participant. A standard breakfast was given to all participants 1 h after dosing. We We performed a sequential pharmacokinetic study. recorded all concurrent medication that could influ- This involved two intensive sessions of pharmacoki- ence plasma drug concentrations via drug-drug netic sampling in patients aged .18 years on MDR- interactions. At both pharmacokinetic sampling TB treatment at Brooklyn Chest Hospital and DP sessions, we sampled blood pre-dose as well as 2, 4, Marais Hospital in Cape Town. 6, 8 and 10 h post-dose. After centrifugation, plasma Between May 2016 and February 2017, we was extracted using a pipette and stored temporarily recruited participants with rifampicin (RMP) resis- on dry ice before being transported to the Division of tant TB who qualified for MDR-TB treatment. At the Clinical Pharmacology at the University of Cape time of the study, the standard MDR treatment Town for storage at À808C. Plasma drug concentra- regimen comprised pyrazinamide (PZA), moxiflox- tions were determined using liquid chromatography acin (MFX), kanamycin, cycloserine (CS) (dosed as tandem-mass spectrometry (LC-MS/MS).20–22 LC- terizidone [TRD]), and either ethionamide or isoni- MS/MS was validated according to guidelines set by azid (INH) depending on the results of the line-probe the US Food and Drug Administration and European assay for katG and inhA mutations identified in the Medicines Agency.23,24 pretreatment sputum culture, which indicated high- We used Stata v15.0 (Stata Corp, College Station, level resistance to INH or low-level resistance to INH TX, USA) to perform non-compartmental pharma- and resistance to ethionamide, respectively.18 Etham- cokinetic and statistical analyses. We determined the butol (EMB) was added if there had been no EMB following pharmacokinetic parameters for each drug exposure in the month before treatment initiation, on both dosing sessions: area under the concentration and the possibility of EMB resistance was considered time curve at 0–10 h (AUC ) using the trapezoidal to be low. We considered patients eligible for 0–10 rule, area under the concentration-time curve extrap- recruitment who were taking whole-tablet MDR olated to infinity (AUC ), half-life, peak concentra- treatment, either for MDR-TB (defined as resistance ‘ tion (C ) and time to C . to both RMP and INH)17 or for RMP-monoresistant max max We regarded pre-dose drug concentrations below TB (resistance to RMP but susceptible to INH). the lower level of quantification (BLQ) to be zero if Two sessions of pharmacokinetic sampling spaced all the pre-dose concentrations for a particular drug approximately 1–3 weeks apart (to allow as little inter-session variability as possible) were completed were BLQ. If any pre-dose concentrations for a drug for each participant 2 weeks after treatment were quantifiable, we then regarded all pre-dose initiation. Drug doses were in accordance with the BLQ concentrations for that drug to be half the national treatment guidelines during the study period lower level of quantification (LLQ). Similarly, post- and adjusted for toxicity before the first session of dose drug concentrations within the sampling pharmacokinetic sampling at the discretion of the interval were unlikely to be zero, so we considered treating clinician.19 any post-dose BLQ results for any of the drugs to be In the case of low-level INH resistance, participants half the LLQ. were given high doses of INH (10–15 mg/kg); the We used the Wilcoxon signed-rank test for paired standard dose of INH (5 mg/kg) was prescribed for data to compare Cmax and AUC0–10 at each session. participants with RMP-monoresistant TB. Partici- Then, the log-transformed values of Cmax and pants were given the same drug doses on both sessions AUC0–10 for exposure to crushed and whole tablets of pharmacokinetic sampling: whole tablets at the were compared with Student’s t-tests. The geometric first session and crushed tablets at the second session. mean ratio (GMR) point estimates and 90% Participants continued with whole-tablet treatment confidence intervals (CIs) of Cmax and AUC0–10 for until the second session of pharmacokinetic sampling, crushed vs. whole tablets were calculated for PZA, when they received crushed tablets; thereafter, they MFX, EMB, INH and CS. continued on whole tablet treatment. Dosing was Approval of our study protocol was granted by the performed under fasting conditions and was strictly Human Research Ethics Committee of the University observed by the study physician or nurse. of Cape Town, Cape Town, South Africa (106/2016). At the second session of pharmacokinetic sam- Written informed consent was taken from each pling, tablets were crushed with a standard-size participant in a language of

Load more