Chapter 5: Pharmacokinetics of high-dose isoniazid for treatment of multidrug resistant
5.5 Discussion
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111 moxifloxacin, and terizidone/cycloserine, the model was unable to distinguish whether the lower exposure was study-specific or due to a DDI with one of these agents in the study regimen. Apart from these three drugs the model was able to distinguish that the other co- administered drugs were not the perpetrator of the DDI in favor of study effect. Similar findings were reported by Winckler et al., 2021 who showed an 80% reduction in isoniazid exposure (median area under the concentration curve (AUC) of 13.1 mg·h/L) in children dosed with isoniazid at 20 mg/kg of as part of an MDR-TB treatment regimen including ethambutol, fluoroquinolones, pyrazinamide, and terizidone, compared to exposures (median AUC 78.1 mg·h/L) in children on an MDR-TB preventive regimen including isoniazid, ethambutol, and fluoroquinolones. The authors postulated that one of the companion MDR-TB drugs could have affected the absorption of isoniazid, specifically terizidone, a structural analogue of cycloserine. Terizidone/cycloserine is postulated to interfere with the absorption of both isoniazid and ethionamide (Global Alliance for TB Drug Development., 2008). A preclinical study observed that ethionamide exposure (AUC) was significantly reduced when co- administered with D-cycloserine but not when the two drugs were administered separately (Ranjan et al., 2019). The chemical structure of ethionamide is similar to that of isoniazid, therefore it is possible that an interaction between both isoniazid and ethionamide exists at the absorption level. If indeed there is an interaction in absorption, dosing isoniazid 12 hours after or before the other MDR-TB drugs might reduce its effect, however this strategy will need further study and might be logistically challenging fordirectly observed therapy.
Drugs whose absorption, distribution, and excretion involve enzymes or carrier-mediated systems are known to saturate at high concentrations (Ludden, 1991). Isoniazid is
112 predominately metabolized (50 – 90%) by NAT2 (Klein et al., 2016b), expressed highest in the liver and gut (Husain et al., 2007). Saturation of this pathway or any other pathway responsible for clearing isoniazid would explain our observed nonlinear pharmacokinetics. A hepatic elimination model characterized the extraction ratio, and saturation was described using Michaelis-Menten kinetics. The model predicts saturation of isoniazid with Km of 19.5 mg/L, and this concentration was only achieved in the liver before first-pass, during the absorption of isoniazid. The nonlinear pharmacokinetics of isoniazid were apparent with doses higher than 10 mg/kg (approximately a 37% and 50% increase in AUC0-24 above linearity at a dose of 15% and 20 mg/kg, respectively) as shown in Figure 5.4.
We report a 29% decrease in the clearance of isoniazid due to the co-administration of ethionamide. This effect was irrespective of the NAT2 phenotype. Ethionamide is a structural analogue of isoniazid, and the two drugs are known to share other similarities like hepatotoxicity, therapeutic targets, and drug resistance (Lehloenya et al., 2015). A study by Chirehwa et al., 2021 found a similar decrease in ethionamide clearance when co- administered with isoniazid. The underlying mechanism for this interaction is unknown, as the two drugs have distinct metabolic pathways (Klein et al., 2016a; Phillips & Shephard, 2017). However, it is possible that the two drugs inhibit each other's clearance pathways in a manner not yet described or compete for the same transporters.
Chirehwa et al. reported a 29% decrease in the AUC24 of isoniazid rapid NAT2 acetylator when co-administered with efavirenz (Chirehwa et al., 2018a). Two other studies reported similar findings (Bhatt et al., 2014; Sekaggya Wiltshire et al., 2014). Our analysis did not detect any substantial change in the exposure of isoniazid when co-administered with efavirenz, possibly
113 due to the small number of rapid NAT2 acetylators and participants on efavirenz-based ART regimens (25%) in these cohorts.
Administration of crushed medication is regularly practiced in some centers, particularly in children who may not tolerate whole tablet formulations. Crushing tablets may affect the absorption and bioavailability of the active drug ingredients (Royal pharmaceurical society, 2011). A non-compartmental analysis of the PODRtb PK data reported a significantly decreased isoniazid exposure when the drug was administered crushed, and mixed with water (Court et al., 2019). Our model estimated that isoniazid reached the systemic circulation faster when it was administered crushed compared to the whole tablet formulation. The bioavailability of crushed or whole isoniazid was comparable. Similar results of faster absorption were reported when comparing the pharmacokinetics of whole versus crushed cycloserine (Chirehwa et al., 2020).
Our study had several limitations, much of which we believe has been mitigated by using a model-based approach for data analysis. NAT2 genotype data was not available for all participants, but this was addressed by imputation using a mixture model to assign the individual with missing information to a phenotype group. Most of the PODRtb patients were on pyrazinamide, moxifloxacin, and cycloserine, Therefore the model was unable to discriminate between the study effect and a potential DDI with these three most common drugs in the PODRtb study. However, the Winckler et al.,(Winckler et al., 2021) study did not observe any interaction between isoniazid and levofloxacin, hence interaction with fluoroquinolones is unexpected. Pyrazinamide is co‐administered with isoniazid for drug‐
sensitive TB treatment, and to our knowledge, no interactions have been reported. Finally, different isoniazid formulations were used in the two studies and, while we expect the two
114 formulations to be bioequivalent, we cannot exclude the effect of the different formulations on the absorption or/and exposure.
In conclusion, our study showed nonlinear pharmacokinetics of isoniazid when dosed above 10 mg/kg. The saturation in isoniazid metabolising enzyme should be considered when recommending doses greater than 10 mg/kg, especially for slow NAT2 acetylators who may have higher isoniazid concentrations and consequently be at increased risk of toxicity.
Additionally, we observed that patients with MDR-TB taking the multidrug treatment had unexpectedly very low isoniazid exposures compared to patients with MDR-TB taking isoniazid alone, an effect which may potentially be due to drug interactions with a companion drug. There is evidence that the interacting drug might be
terizidone/cycloserine, however further investigations are required, especially since the effect is major. The perpetrator of the DDI is not ethionamide, which instead was observed to cause a modest increase in isoniazid exposure when co-administered. This is not likely to be of clinical relevance, except possibly in patients with slow NAT2 acetylator status.
However, further studies are needed on the PK of high-dose isoniazid in patients receiving the WHO shorter regimen, which includes ethionamide but not cycloserine/terizidone.
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