Clinical pharmacology and therapeutic drug monitoring of first-line anti-tuberculosis drugs

Tuberculose (TB of TBC) is een infectieziekte die veroorzaakt wordt door de bacterie Mycobacterium tuberculosis. Als TB niet goed wordt behandeld, zal een groot aantal mensen overlijden aan de ziekte. De behandeling is medicamenteus en bestaat uit een combinatie van antibiotica: isoniazide, rifampicine, pyrazinamide en ethambutol gedurende twee maanden, waarna nog vier maanden moet worden doorbehandeld met isoniazide en rifampicine. Behandeling met deze eerstelijns geneesmiddelen is in het algemeen succesvol, maar resistentie tegen deze middelen en bijwerkingen worden regelmatig gezien. Door de lange behandelduur is daarbij therapietrouw een belangrijk probleem.In dit proefschrift hebben we onderzocht of een geïndividualiseerde of ‘op maat’ manier van doseren van deze geneesmiddelen de kans op een succesvolle behandeling verhoogt.We hebben een literatuuronderzoek gedaan naar de rol van een analysetechniek die veel gebruikt worden voor de kwantitatieve bepaling van geneesmiddelen die gegeven worden bij infectieziekten. We ontwikkelden een gevoelige en snelle analysemethode voor de kwantitatieve bepaling in bloed van isoniazide, pyrazinamide en ethambutol. Verder hebben we een interlaboratorium vergelijkingsprogramma beschreven voor de bepaling van de vier eerstelijns geneesmiddelen en twee tweedelijns geneesmiddelen, moxifloxacine en linezolide, in bloed. Deze tweedelijns geneesmiddelen kunnen worden ingezet als de bacterie resistent is tegen een of meer eerstelijns geneesmiddelen.Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is one of the infectious diseases with the highest morbidity and mortality in the world. In 2014, an estimated 9.6 million people developed TB and 1.5 million people died due to TB. Drug-susceptible TB is treated with the first-line anti-TB drugs, isoniazid, rifampicin, pyrazinamide and ethambutol, during the first two months, continued with isoniazid and rifampicin for another four months. Treatment with the first-line anti-TB drug is challenged by the emergence of drug resistance, toxicity, relapse and non-response.In this thesis, we explored individualized treatment-approaches with conceivably more precision. We described factors to consider when a patient is dosed with first-line anti-TB drugs and proposed methods to optimize treatment in drug-susceptible TB. We performed a literature review on the role of an analysis technique, which is used for the quantification of anti-infective drugs. We developed a sensitive and fast analysis method for the quantification of isoniazid, pyrazinamide and ethambutol in human blood. Furthermore, we described an interlaboratory quality control programme for the measurement of the four first-line anti-TB drugs and two second-line anti-TB drugs, moxifloxacin and linezolid. Second-line anti-TB drugs can be used if the Mycobacterium has developed resistance against one of more of the first-line anti-TB drugs. We developed a method that facilitates prediction of exposure of rifampicin in TB patients. Lastly, we investigated which patient variables influence exposure of isoniazid and rifampicin. We studied the influence of concomitant food intake on the exposure of isoniazid, rifampicin, pyrazinamide and ethambutol

Clinical pharmacology and therapeutic drug monitoring of first-line anti-tuberculosis drugs

Tuberculose (TB of TBC) is een infectieziekte die veroorzaakt wordt door de bacterie Mycobacterium tuberculosis. Als TB niet goed wordt behandeld, zal een groot aantal mensen overlijden aan de ziekte. De behandeling is medicamenteus en bestaat uit een combinatie van antibiotica: isoniazide, rifampicine, pyrazinamide en ethambutol gedurende twee maanden, waarna nog vier maanden moet worden doorbehandeld met isoniazide en rifampicine. Behandeling met deze eerstelijns geneesmiddelen is in het algemeen succesvol, maar resistentie tegen deze middelen en bijwerkingen worden regelmatig gezien. Door de lange behandelduur is daarbij therapietrouw een belangrijk probleem. In dit proefschrift hebben we onderzocht of een geïndividualiseerde of ‘op maat’ manier van doseren van deze geneesmiddelen de kans op een succesvolle behandeling verhoogt. We hebben een literatuuronderzoek gedaan naar de rol van een analysetechniek die veel gebruikt worden voor de kwantitatieve bepaling van geneesmiddelen die gegeven worden bij infectieziekten. We ontwikkelden een gevoelige en snelle analysemethode voor de kwantitatieve bepaling in bloed van isoniazide, pyrazinamide en ethambutol. Verder hebben we een interlaboratorium vergelijkingsprogramma beschreven voor de bepaling van de vier eerstelijns geneesmiddelen en twee tweedelijns geneesmiddelen, moxifloxacine en linezolide, in bloed. Deze tweedelijns geneesmiddelen kunnen worden ingezet als de bacterie resistent is tegen een of meer eerstelijns geneesmiddelen

Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment

Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC0–24h,ss, Cav, Cmax and Cmin) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure–response relationship between linezolid Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a Cmin of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC0–24h should be below 111 h·mg/L or 270 h·mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.</p

Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment

Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC0–24h,ss, Cav, Cmax and Cmin) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure–response relationship between linezolid Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a Cmin of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC0–24h should be below 111 h·mg/L or 270 h·mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.</p

Therapeutic Drug Monitoring of Posaconazole:an Update

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole

Tramadol Steady-State Pharmacokinetics of Immediate-Release Capsules and Sustained-Release Tablets in Dogs

Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs