Thomas Dorlo, Mats Karlsson, Maria Kjellsson, Elin Svensson
Diseases as tuberculosis (TB), HIV and malaria claim 4 million lives every year, the majority in low- and middle-income countries. In the area of global health, we use pharmacometric methodology to support development of new treatments and optimize therapy for these types of infectious diseases.
Better TB treatment for children
About one million children fall ill with TB each year. Model-based analysis is extra valuable for studies in children where is it crucial to characterize the pharmacokinetics from a limited number of sample points. In the network IMPAACT we contribute to design and data analysis of studies aimed to determine optimal dosing regimens for children of different ages, and specifically for children co-infected with HIV and TB.
Through the consortium BenefitKids we investigate new, child-friendly formulations of existing TB drugs. Together with TB Alliance we participate in the pediatric development program for pretomanid, the newest TB drug.
New compounds against multi-drug resistant TB
Development of drug-resistance among bacteria is a global health emergency and multi-drug resistant (MDR) TB is one of the worst forms. We investigate new compounds against MDR-TB and have quantified pharmacokinetic drug-drug interactions for a large number of combinations (1–4). We also demonstrated that model-based analysis is a better method than traditional statistical analyses (5), a result now incorporated in FDA’s guidelines. To enable a better description of concentration-effect relationships in TB we have developed a new type of semi-mechanistic model (see figure) which can describe the bacterial load in the body over time on treatment (6,7).
Simplifying TB treatment
Current standard treatment includes 4 drugs and takes at least 6 months to complete. Together with PanACEA and the research group Pharmacokinetics and Quantitative Pharmacology we participate in several projects aiming to simplify TB treatment. We have investigated if it is possible to shorten treatment duration (8), to give the same dose to all adults instead of using a weight-based schedule (9), and developed methods for evidence-based design of fixed-dose combination tablets (10).
Parasitic infections hit children and pregnant women extra hard, two populations that are typically excluded from clinical trials. Pharmacometric models can be used to optimize treatment for these vulnerable patients. We have investigated how antimalarial drugs should be dosed best in pregnant women (11)and why children have a higher risk of relapse after the end of leishmaniasis treatment (12).
- Svensson EM, Aweeka F, Park J-G, Marzan F, Dooley KE, Karlsson MO. Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis. Antimicrob Agents Chemother. 2013 Jun 1;57(6):2780–7.
- Svensson EM, Dooley KE, Karlsson MO. Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection. Antimicrob Agents Chemother. 2014 Nov;58(11):6406–12.
- Svensson EM, Murray S, Karlsson MO, Dooley KE. Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. J Antimicrob Chemother. 2015 Apr;70(4):1106–14.
- Brill MJE, Svensson EM, Pandie M, Maartens G, Karlsson MO. Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis. Int J Antimicrob Agents. 2017 Feb;49(2):212–7.
- Svensson EM, Acharya C, Clauson B, Dooley KE, Karlsson MO. Pharmacokinetic Interactions for Drugs with a Long Half-Life—Evidence for the Need of Model-Based Analysis. AAPS J. 2016 Jan;18(1):171–9.
- Svensson EM, Karlsson MO. Modelling of mycobacterial load reveals bedaquiline’s exposure-response relationship in patients with drug-resistant TB. J Antimicrob Chemother. 2017 Dec 1;72(12):3398–405.
- Tanneau L, Karlsson MO, Svensson EM. Understanding the drug exposure-response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug-resistant tuberculosis. Br J Clin Pharmacol. 2020 May;86(5):913–22.
- Svensson EM, Svensson RJ, Te Brake LHM, Boeree MJ, Heinrich N, Konsten S, et al. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis. Clin Infect Dis Off. 2018 18;67(1):34–41.
- Susanto BO, Svensson RJ, Svensson EM, Aarnoutse R, Boeree MJ, Simonsson USH. Rifampicin can be given as flat-dosing instead of weight-band dosing. Clin Infect Dis. 2019; Epub ahead of print
- Svensson EM, Yngman G, Denti P, McIlleron H, Kjellsson MC, Karlsson MO. Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy. Clin Pharmacokinet. 2018;57(5):591–9.
- Lohy Das J, Rulisa S, de Vries PJ, Mens PF, Kaligirwa N, Agaba S, et al. Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum Malaria. Antimicrob Agents Chemother. 2018;62(10).
- Dorlo TPC, Kip AE, Younis BM, Ellis SJ, Alves F, Beijnen JH, et al. Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa: a population pharmacokinetic/pharmacodynamic study. J Antimicrob Chemother. 2017 Nov 1;72(11):3131–40.