Catherine J. Lucas

Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.

Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects

There has been a resurgence in interest and use of the cannabis plant for medical purposes. However, an in-depth understanding of plant contaminants and toxin effects on stability of plant compounds and human bioavailability is needed. This systematic review aims to assess current understanding of the contaminants of cannabis and their effect on human health, leading to the identification of knowledge gaps for future investigation. A systematic search of seven indexed biological and biomedical databases and the Cochrane library was undertaken from inception up to December 2017. A qualitative synthesis of filtered results was undertaken after independent assessment for eligibility by two reviewers. The common cannabis contaminants include microbes, heavy metals and pesticides. Their direct human toxicity is poorly quantified but include infection, carcinogenicity, reproductive and developmental impacts. Cannabis dosing formulations and administration routes affect the transformation and bioavailability of contaminants. There may be important pharmacokinetic interactions between the alkaloid active ingredients of cannabis (i.e. phytocannabinoids) and contaminants but these are not yet identified nor quantified. There is significant paucity in the literature describing the prevalence and human impact of cannabis contaminants. Advances in the availability of cannabis globally warrant further research in this area, particularly when being used for patients.

Pharmacokinetic-Guided Dosing of New Oral Cancer Agents

Generally, licensed drug‐dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle‐aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity‐associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese—even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area–guided dosing, therapeutic drug monitoring or pharmacokinetic‐guided dosing, which predicts an individuals exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size–based dosing or “one dose fits all” is used. This review will focus predominantly on the rationale for pharmacokinetic‐guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

Pill testing at music festivals: can we do more harm?

Recently, there have been calls for pill testing to be introduced at music festivals. Advocates say that this would inform consumers and reduce risks. However, there are a number of technical and laboratory limitations of such an intervention that need to be considered. This editorial will highlight these limitations. The recent deaths and hospitalisation of young people from illicit drug use has led to calls for the introduction of on-site testing of tablets and capsules containing illicit drugs (‘pills’) at music festivals and events. Pill testing, both onand off-site, is available in several European countries, with individuals submitting samples for drug identification and purity analysis. These services are aimed at both harm minimisation and providing information on the availability and emergence of new psychoactive substances. Death and morbidity data are unavailable to ascertain the effectiveness or harm of this intervention. Advocates for pill testing argue that by providing information on content, the person can reconsider taking the pill. To support that, an online survey by the Australian National Council on Drugs reported that most young people supported pill testing being available and wanted access to reliable and balanced information so that they would be more equipped to make informed decisions about the risks of using drugs. A field survey of Swiss attendees at dance music events reported that respondents were receptive to harm reduction measures, including pill testing. However, 27.4% responded that they would never use pill testing; 31.1% would use it systematically before taking a pill, and 41.6% would not use unless they did not know the substance, dealer or both. The introduction of pill testing is perceived as a way to monitor pill composition and encourage information exchange. However, it is possible that information received from this may also be seen as affirming the quality and purity of the pill. The testing of illicit drug formulations does not guarantee the safety of the product or protect the person consuming the drug from harm. In a research report on ecstasy pill testing, the authors concluded that pill testing at best gave an artificial ‘shine of safety’, and other simpler harm reduction mechanisms were more likely to be effective. Although some would consider some information better than nothing, false reassurance because of false negative results is a concern. Thus, this editorial focuses on the technical and laboratory limitations of such an intervention. On-site pill testing procedures include pill identification, reagent testing kits and chromatographic techniques. Pill identification relies on visually comparing pills supplied by the consumer with formerly analysed pills. This approach has limited utility if testing is to be performed at different geographically distinct locations. Even if the tablets are similar in appearance, it assumes that each batch contains the same excipients and the same dose and that each tablet in a batch contains a uniform dose or that the same tablet press has not been used to manufacture another batch of tablets containing a different drug. Reagent testing involves mixing a small sample of powder scraped or removed from the illicit drug formulation with chemical reagents to produce a colour change. The class of drug present is identified by the colour produced. Some kits are labelled semi-quantitative and use colour intensity to classify tablet content from very low to very high. Problems with reagent testing include lack of specificity between similar compounds, cross-reactivity with non-related compounds producing incorrect results and the inability to detect other potentially dangerous compounds that may be present. As the distribution of the illicit drug in the tablet may not be uniform, samples taken from multiple scrapings of the same tablet surface may give results varying from little or no drug to high concentration. In terms of actual dose that will be administered, the interpretation of what low or very high means is variable. It may be argued that, given the flaws of pill identification and chemical reagent testing, sophisticated techniques, such as liquid or gas chromatography with mass spectrometry, could be employed for on-site pill testing. These techniques involve expensive and technical equipment and highly trained personnel just to undertake the analytical work. For chromatography to be effectively used, there needs to be a previously determined reference library of drugs, likely contaminants and harmful excipients in a tablet or capsule to which test samples can be matched. Any drug testing method needs to know what drug or chemical it is looking for. Therefore, unknown substances in a preparation may not be detected if the testing method is not set up to detect this. The analysis may find the substance it is looking for but miss a dangerous adulterant or, if a new designer drug is present that is not in the assay library, it could be missed

Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer

BACKGROUND Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. CASE DESCRIPTION A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. RESULTS THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60ng/mL. Evidence suggests that blood THC concentrations >5ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5ng/mL was 49days after administration. DISCUSSION The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy.

Optimal cancer drug dosing in adolescents: new issues and the old unaddressed ones: Editorial

Adolescents and young adults (AYA) with cancer (considered to be 15–25-year olds in Australia) are a population group well known to have emotional and social needs that differ from older adults, best served by specialist AYA oncology services. Although strides have been made in setting up such services in Australia, there are several additional issues regarding AYA that need to be addressed to improve cancer outcomes in this population. One of these is a paucity of knowledge around particular physiological and pharmacological differences in children and adults, which may impact their response to oncological treatments – specifically toxicities and survival – and the second is that there are few physicians trained in adolescent medicine. Critically, there are several new clinical issues facing AYA, which are raising additional issues about the safety and efficacy of dosing in this group. As both under and overdosing of chemotherapy affect survival and late toxicity, clinical research into this area to improve guidance is vital.

Predicting drug interactions in addiction treatment

It is not uncommon to be treating people with addiction who also have significant other health problems, including heart, renal or liver failure, diabetes and vascular disease. These conditions require regular medications to be taken. This can be a problem for people living with addiction and difficult social circumstances affecting compliance, among other issues. Our perspective provides a summary of general pharmacological factors affecting medicine taking in people with addiction problems, to provide a guide for hospital doctors in this setting.

Comment on a paper by Dupoiron et al. “A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone- naloxone (up to 160/80 mg daily) versus oxycodone PR”

(1) This study combines patients with disparate pain aetiologies from both cancer and noncancer pain who have achieved stable pain scores on 100– 160 mg oxycodone daily. These populations are quite different physiologically and phenotypically, with noncancer pain having nonpharmacological options recommended (The Royal Australasian College of Physicians 2009; The British Pain Society 2012; Centers for Disease Control 2016; Busse et al., 2017). (2) The Rentz et al. (2009) publication on validating the Bowel Function Index (BFI) as an assessment tool found that a score of ≥12 is needed to detect clinically meaningful changes in constipation. Dupoiron et al. report a difference in BFI between the OXN PR and OxyPR groups of 16.05, with the top of the confidence interval <12; (CI: 22.23, 9.86) (Dupoiron et al., 2017). Thus, the endpoint of clinically meaningful benefit is of uncertain distinction between the groups. (3) Dupoiron et al. (2017) found that the need for bisacodyl 10 mg rescue laxative medication decreased in both the OXN PR and OxyPR study populations. The requirement by week 5 was 0.6 mg/day in the OXN PR group and 1.2 mg/day in those on OxyPR. Whilst the decreased laxative dose between the groups achieved statistical significance, a dose reduction of 0.6 mg (or a difference of less than one 10 mg dose per week) is unlikely to be clinically relevant. (4) Lastly, we believe the difference in adverse events between the two groups requires further analysis. In the patients on OXN PR, 54.5% experienced at least one adverse event, with 6.5% having a severe treatment-related adverse event. This compares to 47.5% total and 4.2% severe treatment-related side effects in the OxyPR group. Although a statistically significant difference is difficult to elicit using reporting of adverse events in a study underpowered for this endpoint, there is a consistent numerical difference. Of particular interest, the incidences of the common opiate withdrawal symptoms, hyperhidrosis, nausea, restlessness and ‘drug withdrawal syndrome’ were higher in the OXN PR group. Further discussion on the incidence, frequency and persistence of naloxone-related adverse events is of significant interest to clinicians considering using these therapies.