Research: pediatric meningitis dosing; cancer drug resistance; gene-testing economics

Computer models provide optimal dosing for pediatric TB meningitis

Tuberculous meningitis (TBM) is an inflammation of membranes lining the brain and spine (central nervous system, CNS) due to infection with TB bacteria. TBM is especially devastating in young children, in whom it is most common, carrying a high risk of death or severe neurologic impairments. But pediatric TBM drug regimens vary widely by country and the only clinical trial evaluating dosing in children was done 30 years ago.

UCSF School of Pharmacy faculty member Rada Savic, PhD, was lead author of a paper in the December issue of Clinical Pharmacology and Therapeutics that sought to determine the optimal dosing of drugs to treat TBM in children. The study used computation to model the potential effects of drug therapies, including how drugs are processed by the body (pharmacokinetics, PK) and the extent to which they reach and affect disease targets (pharmacodynamics, PD).

Savic and her co-authors from around the world (India, Indonesia, South Africa, the Netherlands) combined data from recent adult studies—which used higher doses of certain antibiotics to increase blood concentrations, better penetrate the CNS, and reduce deaths—with data on how children treated for TB differentially process those antibiotics. The results of the PK/PD analyses and computer-simulated clinical trials led to new recommended pediatric doses of some antibiotics in a four-drug regimen to more effectively treat TBM—including higher weight-proportional doses of two drugs (rifampin, levofloxacin) for children than for adults to achieve effective CNS infection site drug exposures. These recommendations provide the basis for upcoming trials to confirm their safety and efficacy.

Savic is a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

Journal Citation: Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, Swaminathan S, McIlleron H, Gupta A, van Crevel R, Dooley KE, “Pediatric Tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children,” Clinical Pharmacology and Therapeutics, Vol. 98, p. 622-629.

Persister cancer cells: From drug tolerance to diverse drug resistance

Much cancer research focuses on eliminating the disease’s fast-growing cells. But there is increasing evidence that entry into a slow-growing “persister” state may allow small subpopulations of cancer cells to survive and tolerate initial drug treatment. Then, much as is seen with the disease’s clinical recurrence after remission, after weeks to months of negligible growth those persister cells may resume rapid division and proliferation despite continued drug treatment—a state of drug resistance.

Steven Altschuler, PhD and Lani Wu, PhD, faculty members in the School’s Department of Pharmaceutical Chemistry, senior-authored a paper published in February in Nature Communications that demonstrated for the first time that cells emerging from the slow-growing persister state can display a diverse range of drug-resistance mechanisms. In fact, the initial stage of glacial growth amid drug treatment does not limit the emergence of diverse modes of drug resistance leading to resurgent proliferation. Instead, these persisters provide a latent reservoir of cells that probably acquire such diverse resistance via genetic mutation during their slower replication over many months.

Altschuler, Wu, and their co-authors began by cloning a single lung cancer cell to generate a nearly identical population of cells with exquisite sensitivity to a drug (erlotinib) targeting an aberrant receptor. The vast majority of cells were eradicated by a high dose of the drug, and even the surviving cells—the persisters—initially exhibited extremely slow growth while being constantly exposed to the drug. Over the course of nearly a year of constant drug treatment, 17 colonies of persister lung cancer cells that had been isolated for study regained the ability to more rapidly proliferate.

To understand the evolved resistance to erlotinib, the researchers analyzed both the colonies’ genomes and their responses to hundreds of additional anti-cancer drugs. The researchers found that the colonies had probably acquired and were now exhibiting a diverse range of genetically-driven resistance mechanisms, many of them of the same types seen clinically in patients.

Journal citation: Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA, Morinishi LS, Evans L, Ji W, Hsu C-H, Thurley K, Wei S, Zhou A, Koduru, PR, Posner BA, Wu LF, Altschuler SJ, “Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells,” Nature Communications, Feb. 19, 2016, Vol. 7, p. 1-8.

Analysis finds evidence lacking on cost effectiveness of gene screens

The screening of patients’ genes for mutations related to disease is increasingly moving from the lab to the clinic. Indeed, such mutations may turn up in analysis of a patient’s entire genome (whole genome sequencing), which is becoming increasingly affordable. While this screening is now done only in select cases, it may eventually become routine practice.

These developments are raising urgent questions about public health policy. For example, suppose a gene mutation related to a health condition is recommended as “clinically actionable” by the American College of Medical Genetics and Genomics (ACMG)—meaning a treatment or behavior change could improve health outcomes. Is it cost effective to test for that mutation in the general population or even in high-risk groups? That is, how many added years of healthy life will such genetic screening provide to each patient in a population, relative to the millions of dollars in overall costs?

Such evidence base questions are regularly addressed by the Center for Translational and Policy Research on Personalized Medicine (TRANSPERS), based in the School’s Department of Clinical Pharmacy. TRANSPERS founding director and School faculty member Kathryn Phillips, PhD, senior-authored a paper in the February issue of Genetics in Medicine that searched the past generation of scientific literature (1994-2014) for studies of the cost effectiveness of screening for the 56 gene mutations related to 24 conditions that the ACMG deems actionable if found during whole genome sequencing. Kathryn and her co-authors found the cost effectiveness of screening the general population had been addressed in only two of the two dozen conditions and of screening high-risk populations in only seven conditions.

Journal Citation: Douglas MP, Ladabaum U, Pletcher MJ, Marshall DA, Phillips KA, “Economic evidence on identifying clinically actionable findings with whole-genome sequencing: a scoping review,” Genetics in Medicine, Feb. 2016, Vol. 18, p. 111-116.

About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.