New thesis provides important knowledge in war on tuberculosis

Since the 1960s, only a handful of drugs have been developed against tuberculosis, and every year 1.5 million people die as a result of resistant tuberculosis bacteria. Today, the threat is increasing across the Baltic Sea, and the need for tools to slow the rapid spread of the disease is urgent. In Europe, knowledge consortia ERA4TB and UNITE4TB lead the work where Uppsala University's research group in pharmacokinetics – the only one to be engaged in both initiatives – has the important task to develop mathematical models for the design and calculated outcome of clinical studies. In a new PhD thesis, Budi Octasari Susanto presents findings with the capacity to contribute to more effective drug development and optimized treatments.

“Among our priority challenges is the ability to already in the laboratory estimate the effects of potential combination treatments in the human body. To do this during a clinical phase 2 study will consume unnecessary resources, and by applying different combinations of rifampicin and isoniazid to bacteria and adding preclinical and clinical information, we can now present a method that contributes to already at a preclinical stage predict optimal dosage,” says Budi Octasari Susanto, PhD student at the Department of Pharmaceutical biosciences.

In a study focusing on drug development, the group have evaluated uptake in the body while using different formulations of macozinone, a drug candidate that is poorly soluble in water. By developing and using a mathematical model, Budi Octasari Susanto has managed to establish that spray-dried dispersion is the choice of formulation that generates the highest concentration in the blood.

“Our ambition is to add valuable tools for early calculation of optimal dosage in combination treatments and to choose the best drug formulation in order to enhance absorption in the body. We are also identifying opportunities to further develop our new models with the aim to enable calculation of the effect of treatments combining three or more drugs as well as the possibility to predict the efficiacy of future clinical studies.”

In her thesis, Susanto also highlights the treatment of tuberculosis with the drug rifampicin. Caregivers often adjust dosages based on the patient's body weight, but by using computer simulation, Susanto shows that the drug concentration in the blood will not be significantly affected by giving all care recipients identical doses, an alternative that simplifies the care provider's work without affecting the result.

“Numerous studies also show that the recommended dose of rifampicin is insufficient to treat tuberculosis. In parallel, we know that an increase to a sufficient dose can cause patients to develop drug intolerance. Thus, we have explored an alternative strategy with incrementally increased dosage, which indicates both safer and more effective concentrations of rifampicin in the blood. All in all, I hope that my thesis will add relevant knowledge to the ongoing efforts to stop tuberculosis as a threat to global public health,” concludes Budi Octasari Susanto.

text: Magnus Alsne, photo: private, Leonardo