By Christie Budd BVSc MVSc
My favourite social media moments of this year were from #marchforscience; librarians, scientists and academics holding signs like “cite your sources or go home”. Well, we now have enough peer-reviewed publications under our belt in this field that we felt it was time to summarise what we have learnt in this decade.
Our research group has performed koala specific pharmacokinetic (PK) investigations of the following antibacterials: enrofloxacin, marbofloxacin, chloramphenicol, florfenicol and cefovecin; two antifungals fluconazole and posaconazole; and the non-steroidal anti-inflammatory (NSAID) meloxicam.
Our research has led to more questions than answers, but we have identified important trends emerging from the data. The papers we write require access to academic literature, and they make for extremely tedious (and generally incomprehensible) reading. To celebrate the acceptance of our review article on antibacterials and antifungals in the Journal of Veterinary Pharmacology and Therapeutics (Govendir M. Review of some pharmacokinetic and pharmacodynamic properties of anti-infective medicines administered to the koala (Phascolarctos cinereus). Journal of Veterinary Pharmacolology and Therapeutics 2017;00: 1–10. https://doi.org/10.1111/jvp.12435) we thought we would write about some of the findings in a way everyone can understand.
Adult koalas are the size of the average cat or small dog (approximately 3-14 kg) and being cute and furry, they are also mammals, just like us. But that is about where the similarities cease. Dogs are cats are both carnivorous predators, who have lived closely alongside humans for thousands of years. Koalas are not just vegetarians, they are highly specialised folivores- eating the leaves of a limited number of tree species (mostly eucalypts). They spend most of their time high in trees and despite their teddy bear-like appearance, are wild animals. In order to survive on a diet of leaves, full of chemicals which are toxic to most insects and animals, you need some pretty specialised body adaptations. Under their fluffy exterior, that cute, round tummy, is essentially just a huge fermentation chamber and amazing liver. Their large intestine has a massive caecum, where a rich mix of microbes do much of the work of turning relatively indigestible and poisonous leaf material into nutrients the koala can use. The liver is responsible for converting toxins absorbed from the leaf into harmless products that can be excreted as waste. Just in case you have ever wondered, yes, koala urine and poo does smell quite a lot like eucalyptus.
We have talked previously about the important role of gut microbes to koala health and digestion, and the extreme dangers that antibiotics pose to gut microbes, through their propensity to kill all the “good” gut microbes and being generally poor at killing chlamydia which hides away, inside cells, protected from most antibiotics.
In this post we want to examine some of the PK factors which make treating koalas so challenging. Pharmacokinetics sounds really scary, but it is just an attempt to mathematically describe the processes of how a particular animal species absorbs, distributes, metabolises and then excretes medicines. Absorption being the process of getting the drug inside the body, distribution looks at where it goes inside the body and how fast it moves there, metabolism is the process by which drugs are altered, so that it is easy for the body to get rid of them. Absorption and distribution are concepts that are pretty easy to understand- but metabolism sounds a bit mysterious. For our pharmacokinetic purposes here, it is sufficient to think of drug metabolism and excretion as being similar to what you might do to all the prawn heads left over from a seafood BBQ. You don’t just chuck them in the trash on Saturday night, knowing that the garbage won’t be collected until Friday morning- yuk- toxic mess! What you might do instead is wrap them in several layers of newspaper, then double-wrap them in biodegradable bags, place them in the freezer until Thursday morning, then dump them in the green bin. Well, depending on the type of drug, the liver may do nothing, or go through a whole series of elaborate steps so your waste products can be safely dumped the next time you visit the bathroom. That is as much about PK as you need to know.
We would like to give koalas their medicine by mouth or as an injection under the skin, as these are fairly safe and easy methods for both koalas and the people who care for them. “How’s that working?” you ask; not great. Absorption of the drugs we have studied after administration to koalas has generally been poor to very low and highly variable between individuals. Poor absorption limits the amount of drug available to have an effect in the body. The combined processes of metabolism and excretion are referred to as clearance rates. Scientists hate to make predictions, they prefer to do experiments to find out what actually happens, not what we think might happen, but had we been forced to predict, we might have expected that koalas would be able to rapidly clear any kind of medicine. We would have been wrong. Koalas clear meloxicam ( non-steroidal anti-inflammatory) extremely rapidly compared to other species, and can briskly clear fluconazole also (anti-fungal) yet their clearance rates of enrofloxacin and chloramphenicol are about average. The clearance of both chloramphenicol and fluconazole appear to have been at least partially limited by the rate at which the drugs are absorbed and subsequently presented to the liver.
So what advice can we give to vets who are responsible for treating and/or prescribing medicines to koalas- that there are no hard and fast rules unfortunately. Can we make useful predictions yet about medicines being used in koalas that we haven’t subject to PK investigation? The short answer is no. With the exception of orally administered posaconazole, it seems that drug absorption after giving treatments by mouth or under the skin are unlikely to reach the same levels in the blood that we would see in people and other animals, and that is probably the biggest PK challenge to koala medicine. Secondly, koalas will probably be able to clear some types of drugs extremely rapidly, but not necessarily all, so we can’t always assume we have to give koalas much higher dose rates than other animals. With more investigation, using in-vitro techniques (rather than live animals) we hope to be able to make more informed guesses about which drugs they are likely to clear at a faster rate than other animals.
We realise this is all very frustrating to people who are faced with sick and traumatised koalas who require help now, but limited funding for wildlife medicine and the slow pace of rigorous science limits our progress. We are however, committed to sharing everything we learn as soon as we discover it. So please share these articles and links with anyone who may be interested and if you are on the frontline treating koalas, please feel free to contact us with any questions. You can send us messages and questions via our Facebook page.
For the academics, scientists, pharmacologists and other geeks out there, read our papers- our references are proudly cited below.
Black, L. A., Higgins, D. P., & Govendir, M. (2015). In vitro activities of chloramphenicol, florfenicol and enrofloxacin against Chlamydia peco- rum isolated from koalas (Pharcolarctos cinereus). Australian Veterinary Journal, 93, 420–423.
Black, L. A., Krockenberger, M. B., Kimble, B., & Govendir, M. (2014). Pharmacokinetics of fluconazole following intravenous and oral ad- ministration to koalas (Phascolarctos cinereus). Journal of Veterinary Pharmacology and Therapeutics, 37, 90–98.
Black, L. A., Landersdorfer, C., Bulitta, J., Griffith, J. E., & Govendir, M. (2014). Evaluation of enrofloxacin use in koalas (Phascolarctos cinereus) via population pharmacokinetics and Monte Carlo simulation. Journal of Veterinary Pharmacology and Therapeutics, 37, 301–311.
Black, L. A., McLachlan, A. J., Griffith, J. E., Higgins, D. P., Gillett, A., Krockenberger, M. B., & Govendir, M. (2013). Pharmacokinetics of chloramphenicol following administration of intravenous and subcuta- neous chloramphenicol succinate, and subcutaneous chloramphenicol, to koalas (Phascolarctos cinereus). Journal of Veterinary Pharmacology and Therapeutics, 36, 478–485.
Black LA. Aspects of the pharmacokinetics and pharmacodynamics of chloramphenicol, enrofloxacin and fluconazole in koalas (Phascolarctos cinereus). PhD thesis 2013. http://ses.library.usyd.edu.au/handle/2123/11597
Budd, C., Flanagan, C., Gillett, A., Hanger, J., Loader, J. J., & Govendir, M. (2017) Assessment of florfenicol as a possible treatment for chlamydiosis in koalas (Phascolarctos cinereus). Australian Veterinary Journal, in press.
Gharibi S, Kimble B, Vogelnest L, Barnes J, Stadler CK, Govendir M. Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration. Journal of Veterinary Pharmacology and Therapeutics. 2017;00:1–7. https://doi.org/10.1111/jvp.12407
Govendir M. Review of some pharmacokinetic and pharmacodynamic properties of anti-infective medicines administered to the koala (Phascolarctos cinereus). Journal of Veterinary Pharmacolology and Therapeutics 2017;00: 1–10. https://doi.org/10.1111/jvp.12435
Govendir, M., Black, L. A., Jobbins, S., Kimble, B., Malik, R., & Krockenberger, M. B. (2016). Some pharmacokinetic indices of oral fluconazole ad ministration to koalas (Phascolarctos cinereus) infected with crypto coccosis. Journal of Veterinary Pharmacology and Therapeutics, 39, 412–415.
Govendir, M., Hanger, J., Loader, J. J., Kimble, B., Griffith, J. E., Black, L. A., … Higgins, D. P. (2012). Plasma concentrations of chloramphenicol after subcutaneous administration to koalas (Phascolarctos cinereus) with chlamydiosis. Journal of Veterinary Pharmacology and Therapeutics, 35, 147–154.
Griffith, J. E. (2010). Studies into the diagnosis, treatment and management of chlamydiosis. Doctor of Philosophy (PhD) The University of Sydney, Australia. https://ses.library.usyd.edu.au/handle/2123/6836
Griffith, J. E., Higgins, D. P., Li, K. M., Krockenberger, M. B., & Govendir, M. (2010). Absorption of enrofloxacin and marbofloxacin after oral and subcutaneous administration in diseased koalas (Phascolarctos cinereus). Journal of Veterinary Pharmacology and Therapeutics, 33, 595–604.
Kimble B, Li KM, Govendir M. Quantitation of meloxicam in the plasma of koalas (Phascolarctos cinereus) by improved high performance liquid chromatography Journal of Veterinary Science 2013;14:7-14.
Kimble B, Li KM, Valtchev P et al. In vitro metabolism of meloxicam in koalas (Phascolarctos cinereus), brushtail possums (Trichosurus vulpecula), ringtail possums (Pseudocheirus peregrinus), rats and dogs. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 2014;161:7-17.
Kimble B, Black LA, Li KM et al. Pharmacokinetics of meloxicam in koalas (Phascolartos cinereus) after intravenous, subcutaneous and oral administration. J Vet Pharmacol Ther 2013;36:486-493.
Kimble B. Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species. PhD thesis The University of Sydney, Australia, 2015. https://ses.library.usyd.edu.au/handle/2123/13996