Browsing by Author "Calcagno, Andrea"

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    High efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults with a CYP2B6 516 TT genotype on anti-TB treatment
    (Journal of Antimicrobial Chemotherapy, 2019) Braun, Amrei von; Castelnuovo, Barbara; Ledergerber, Bruno; Cusato, Jessica; Buzibye, Allan; Kambugu, Andrew; Fehr, Jan; Calcagno, Andrea; Lamorde, Mohammed; Sekaggya-Wiltshire, Christine
    To report the efavirenz serumconcentrations in TB/HIV-coinfected Ugandan adults on concomitant anti-TB treatment and analyse factors associated with elevated concentrations in this specific population. Methods: Serum efavirenz concentrations in TB/HIV-coinfected Ugandan adults on efavirenz-based ART (600mg daily) were measured onsite at 2, 8, 12 and 24 weeks of concomitant anti-TB treatment, including rifampicin. Genetic analysis was done retrospectively through real-time PCR by allelic discrimination (CYP2B6 516G.T, rs3745274). Univariable and multivariable logistic regression analyses were done to assess factors potentially associated with elevated efavirenz serum concentrations. Results: A total of 166 patients were included in the analysis. The median age was 34 (IQR"30–40) years, 99 (59.6%) were male, the median CD4 cell count was 195 (IQR"71–334) cells/mm3 and the median BMI was 19 (IQR"17.6–21.5) kg/m2. Almost half of all patients (82, 49.4%) had at least one efavirenz serum concentration above the reference range of 4 mg/L. The serum efavirenz concentrations of patients with genotype CYP2B6 516 TT were consistently above 4 mg/L and significantly higher than those of patients with GG/GT genotypes: CYP2B6 516 TT 9.6 mg/L (IQR"7.3–13.3) versus CYP2B6 516 GT 3.4 mg/L (IQR"2.1–5.1) and CYP2B6 516 GG 2.6 mg/L (IQR"1.3–4.0) (Wilcoxon rank-sumtest: P,0.0001). Conclusions: A large proportion of our study participants had at least one efavirenz serum concentration .4 mg/L. The CYP2B6 516 TT genotype was the strongest predictor of high concentration. Physicians should be vigilant that efavirenz serum concentrations may be elevated in patients on concomitant anti-TB treatment and that individualized care is warranted whenever possible.
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    Low Antituberculosis Drug Concentrations in HIV-Tuberculosis- Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?
    (Antimicrob Agents Chemother, 2019) Sekaggya-Wiltshire, Christine; Chirehwa, Maxwell; Musaazi, Joseph; Braun, Amrei von; Buzibye, Allan; Muller, Daniel; Gutteck, Ursula; Motta, Ilaria; Calcagno, Andrea; Fehr, Jan S.; Kambugu, Andrew; Castelnuovo, Barbara; Lamorde, Mohammed; Denti, Paolo
    Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing 55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)