Population variability in animal health: Influence on dose‐exposure‐response relationships: Part II: Modelling and simulation

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1‐day session on the influence of population variability on dose‐exposure‐response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals.     

Development of a limited‐sampling model for prediction of doxorubicin exposure in dogs

Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited‐sampling strategy for DOX, in which three blood samples are obtained over 1 h post‐treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.     

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between‐patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food‐producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population‐associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.     

P‐Glycoprotein Mediated Drug Interactions in Animals and Humans with Cancer

Drug–drug interactions can cause unanticipated patient morbidity and mortality. The consequences of drug–drug interactions can be especially severe when anticancer drugs are involved because of their narrow therapeutic index. Veterinary clinicians have traditionally been taught that drug–drug interactions result from alterations in drug metabolism, renal excretion or protein binding. More recently, drug–drug interactions resulting from inhibition of P‐glycoprotein‐mediated drug transport have been identified in both human and veterinary patients. Many drugs commonly used in veterinary patients are capable of inhibiting P‐glycoprotein function and thereby causing an interaction that results in severe chemotherapeutic drug toxicity. The intent of this review is to describe the mechanism and clinical implications of drug–drug interactions involving P‐glycoprotein and anticancer drugs. Equipped with this information, veterinarians can prevent serious drug–drug interactions by selecting alternate drugs or adjusting the dose of interacting drugs.     

Patient variation in veterinary medicine--part II--influence of physiological variables

In veterinary medicine, the characterization of a drug's pharmacokinetic properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. In Part I of the series, we focused on the potential influence of disease processes, stress, pregnancy and lactation on drug pharmacokinetics. In this Part II of the series, we consider other covariates, such as gender, heritable traits, age, body composition, and circadian rhythms. The impact of these factors with respect to predicting the relationship between dose and drug exposure characteristics within an animal population is illustrated through the use of Monte Carlo simulations. Ultimately, an appreciation of these potential influences will improve the prediction of situations when dose adjustments may be appropriate.     

Population pharmacokinetics in veterinary medicine: Potential use for therapeutic drug monitoring and prediction of tissue residues

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).     

The pharmacogenomics of P-glycoprotein and its role in veterinary medicine

Despite advancements in pharmacogenetics in human medicine, the incorporation of pharmacogenetics into veterinary medicine is still in its early stages of development. To date, efforts to understand the pharmacologic impact of genetic variation in veterinary species have largely focused on genes encoding for the membrane transporter, P-glycoprotein (P-gp). The emphasis on the role of P-gp is largely because of safety concerns associated with the use of some macrocyclic lactones in dogs. Because of the body of information available on this topic, we use P-gp as a platform for understanding the importance of population diversity in veterinary medicine. The impact of P-gp on drug pharmacokinetics and pharmacodynamics is considered, along with endogenous and exogenous factors that can modulate P-gp activity. The review includes discussion of how population diversity in P-gp activity can lead to susceptibility to certain diseases or alter patient response to environmental stress or pharmaceutical intervention. In addition, phenotypic diversity also needs to be considered, as demonstrated by the impact of P-gp up-regulation and drug resistance. The aim of this review was to set the stage for further exploration into the impact of genetic and phenotypic variability on drug pharmacokinetics, disease propensity, product formulation and drug response in both companion and food-producing animals.     

Use of a Dose–Response Model to Study Temporal Trends in Spatial Exposure to Coxiella burnetii: Analysis of a Multiyear Outbreak of Q Fever

The Netherlands underwent a large Q fever outbreak between 2007 and 2009. In this paper, we study spatial and temporal Coxiella burnetii exposure trends during this large outbreak as well as validate outcomes against other published studies and provide evidence to support hypotheses on the causes of the outbreak. To achieve this, we develop a framework using a dose–response model to translate acute Q fever case incidence into exposure estimates. More specifically, we incorporate a geostatistical model that accounts for spatial and temporal correlation of exposure estimates from a human Q fever dose–response model to quantify exposure trends during the outbreak. The 2051 cases, with the corresponding age, gender and residential addresses, reside in the region with the highest attack rates during the outbreak in the Netherlands between 2006 and 2009. We conclude that the multiyear outbreak in the Netherlands is caused by sustained release of infectious bacteria from the same sources, which suggests that earlier implementation of interventions may have prevented many of the cases. The model predicts the risk of infection and acute symptomatic Q fever from multiple exposure sources during a multiple‐year outbreak providing a robust, evidence‐based methodology to support decision‐making and intervention design.     

Nutrient–drug interactions in nutritional support

Abstract Objective: To review the types and potential consequences of diet/nutrient–drug interactions that can occur in patients receiving nutritional support. Data sources: A literature review was performed using Ovid multi‐database searching including Medline, Agricola and Biosis. Summary: Although very little information is currently available that pertains specifically to veterinary patients, we know from the human experience that food intake and diet composition can affect the absorption, distribution, metabolism, efficacy and toxicity of a drug. Conversely, certain drugs can alter the absorption of nutrients when administered in conjunction with food or act to antagonize nutrient metabolism or function. The different ways that incompatibility can arise between food or nutrients and drugs in patients receiving nutritional support and strategies for avoiding these problems are discussed. Conclusions: The consequences of diet/nutrient–drug interactions include decreased tolerance of nutritional support, loss of feeding access, decreased drug efficacy, nutrient malabsorption or malassimilation, and risk of drug overdosage. Therefore, when patients receiving nutritional support experience these types of complications, a review of the diet, route of nutritional support, drugs, and timing of feeding and medication administration are indicated.     

Canine acute leukaemia: 50 cases (1989–2014)

Acute leukaemia (AL) is a bone marrow malignancy of hematopoietic progenitors that historically is poorly responsive to treatment. With the widespread adoption of dose‐intense chemotherapy, more human patients attain long‐term survivals, but whether comparable progress has been made in canine AL is unknown. To investigate this question, medical records from three academic veterinary hospitals were reviewed. Fifty dogs met the criteria for AL, having excess circulating or marrow blasts, a major cytopenia(s), and no substantial lymphadenopathy. Thirty‐six dogs received cytotoxic chemotherapy; 23 achieved a complete or partial response for a median of 56 days (range, 9–218). With failure or relapse, 14 dogs were rescued. Median survival with treatment was poor at 55 days (range, 1–300). Untreated (n = 6) and palliatively‐treated (n = 8) dogs lived a median of 7.5 days. Most dogs developed chemoresistance within weeks of initiating treatment, and consequently, survival times for AL remain disappointingly short.     

Supraventricular tachycardia in dogs: 65 cases (1990–2007)

Objective – To characterize the signalment, clinical findings, and prognosis of dogs with supraventricular tachycardia (SVT). Design – Retrospective study. Setting – North Carolina State University Veterinary Teaching Hospital. Animals, Intervention, and Measurements – Case selection included all patients at the veterinary teaching hospital with SVT during years 1990–2007. Medical records from dogs with at least 1 recorded episode of SVT were extracted. The signalment, history, electrocardiographic, radiographic, and echocardiographic findings, therapy, and response to therapy were reviewed and summarized. Follow‐up was conducted to determine the date and cause of death. Kaplan‐Meier survival curves were constructed and analyzed. The relationships between patient characteristics and responses to therapy and prognosis were evaluated. Main Results – Sixty‐five records documented a diagnosis of SVT. Sixty‐two percent were males. Labrador Retrievers and Boxers were overrepresented compared with the general hospital population. Median age at presentation was 9 years (range 0.5–15.5 y). The median heart rate during SVT was 270/minute (range 187–375/min). The most common presenting complaint was syncope (30%), 23% were asymptomatic at the time of diagnosis. Most dogs had structural heart disease (65%). Median survival was 472 days (<1–2007 d). Identification of sustained SVT (>30 s) did not affect survival (P=0.50), nor did the presence of congestive heart failure (P=0.70). Conclusions – The majority of dogs with SVT had structural heart disease or a severe concurrent illness at the time of SVT diagnosis. SVT, though often a persistent and occasionally sustained arrhythmia, does not appear to be a primary factor in mortality.     

How to extrapolate a withdrawal time from an EHSLC published detection time: A Monte Carlo simulation appraisal

Reason for performing study: For legitimate medications, veterinarians must advise the owners or trainers of horses on appropriate withholding times after a treatment, to avoid the risk of incurring a positive drug test. Objective: To explore the safety span to select that a veterinarian may extrapolate a tailored withdrawal time (WT) from a generic detection time (DT) as published by the European Horserace Scientific Liaison Committee (EHSLC). Methods: Using Monte Carlo simulations, it was shown that for a low variability of pharmacokinetic parameters (CV = 20%), an uncertainty span of about 40% may be selected to transform a mean DT into a WT (i.e. WT = 1.4 DT), which covers 90% of the horse population. In contrast for a highly variable drug (CV = 40%), an uncertainty factor of about 2.1–2.2 needs to be selected, i.e. a WT that is twice the DT. Results: The relative impact of the different factors of variability on the final WT was documented by a so‐called sensitivity analysis. It was shown that the parameters that have the greatest influence on the value of a DT are those that control the terminal half‐life of the drug disposition. In contrast, parameters controlling the level of urine (or plasma) concentrations (i.e. the actual administered dose, the urine‐to‐plasma ratio and the bioavailability) collectively have a minimal influence on the DT. Conclusions and potential relevance: In practice, this means that the main sources of uncertainty are of biological origin and cannot be reduced by any managerial options. The influence of the number of experimental horses that are used by EHSLC to establish a DT was shown that with the standard EHLSC protocol of 6 horses, half of the trials lead to a proposed DT that is equal to or higher than the population 90^th percentile. Increasing the number of investigated horses to 8 and 10 would increase this last probability to 85 and 90%, respectively.     

Multiple comparison procedure and modeling: a versatile tool for evaluating dose–response relationships in veterinary pharmacology – a case study with furosemide

Congestive heart failure (CHF) is a leading cause of mortality with an increasing prevalence in human and canine populations. While furosemide is a loop diuretic prescribed for the majority of CHF patients to reduce fluid retention, it also activates the renin–angiotensin aldosterone system (RAAS) which further contributes to the accelerated progression of heart failure. Our objective was to quantify the effect of furosemide on diuresis, renin activity (RA), and aldosterone (AL) in dogs, using a combined multiple comparisons and model‐based approach (MCP‐Mod). Twenty‐four healthy beagle dogs were allocated to four treatment groups (saline vs. furosemide 1, 2, and 4 mg/kg i.m., q12 h for 5 days). Data from RA and AL values at furosemide trough concentrations, as well as 24‐h Diuresis, were analyzed using the MCP‐Mod procedure. A combination of E_max models adequately described the dose–response relationships of furosemide for the various endpoints. The dose–response curves of RA and AL were found to be well in agreement, with an apparent shallower slope compared with 24‐h Diuresis. The research presented herein constitutes the first application of MCP‐Mod in Veterinary Medicine. Our data show that furosemide produces a submaximal effect on diuresis at doses lower than those identified to activate the circulating RAAS.     

Pharmacogenetics of opioid analgesics in dogs

Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs.     

Vascular-targeted photodynamic therapy (VTP) of a canine-transmissible venereal tumour in a murine model with Pd-bacteriopheophorbide (WST09)

Treatment of canine‐transmissible venereal tumour (CTVT) with local vascular‐targeted photodynamic therapy (VTP) using Pd‐bacteriopheophorbide (WST09) as a drug is suggested as an alternative to conventional chemotherapy. Male CD1 nude mice were subcutaneously grafted with the xenograft‐transmissible canine venereal tumour (XTVT). The VTP protocol delivered once consisted of intravenous administration of WST09 (10 mg kg^?1) followed by immediate local illumination with a diode laser (763 nm). Controls included animals treated with light or WST09 alone. Macroscopic and microscopic evaluations of tumour response were conducted 10, 24 and 48 h after treatment. Upon VTP, tumours underwent necrosis that lasted 8–10 days and exhibited complete healing by 25–35 days, reaching an overall long‐term cure rate (83%) by 90 days after treatment. This study suggests that VTP with WST09 can efficiently treat CTVT in a single session, as compared with 4–6 sessions of chemotherapy and thus may be feasible for common veterinary practice, particularly under ambulatory conditions.     

A comparison of 12‐ and 19‐week CHOP protocols using non‐randomized,contemporaneous controls

This study is a concurrent comparison of two versions of CHOP protocols, a 19‐week CHOP and a comparatively overall dose‐intense 12‐week CHOP. The 12‐week protocol was designed to be 58% more dose intense than the 19‐week protocol for both doxorubicin and cyclophosphamide; however, it was 21% less dose intense for vincristine (VCR). Forty‐seven dogs were included for evaluation, and the characteristics of each population were similar. For dogs receiving the 19‐week CHOP protocol, 89.5% experienced a complete response, with a median progression‐free survival (PFS) of 245 days and median overall survival (OS) of 347 days. For dogs receiving the 12‐week CHOP protocol, 89.3% experienced a complete response, with a median PFS of 141 days and median OS of 229 days. When evaluated by Log‐rank analysis, the difference of PFS (P = 0.047) and OS (P = 0.013) between the groups were statistically significant. In summary, these data suggest that despite overall increased dose‐intensity, dogs receiving treatment with a 12‐week CHOP protocol experience less durable remission than our standard 19‐week protocol in this population. Additional prospective investigation will be required to explore the implication that VCR dose intensity and/or shorter overall temporal drug exposure in this protocol may result in diminished efficacy.     

Lactate: physiology and clinical utility

Objective: To review the physiology of lactate production and metabolism, the causes of lactic acidosis, and the current applications of lactate monitoring in humans and animals. Data sources: Human and veterinary studies. Summary: Lactate production is the result of anaerobic metabolism. Tissue hypoxia due to hypoperfusion is the most common cause of lactic acidosis. Studies in critically ill humans have shown that serial lactate monitoring can be used to assess the severity of illness and response to therapy. Several veterinary studies have also shown lactate as a useful tool to assess severity of illness. Conclusions: Lactate measurement in critically ill veterinary patients is practical and can provide information to assess severity of illness. Further veterinary studies are needed to establish the value of serial lactate measurements for prognostic and therapeutic purposes. Information regarding lactate measurement in cats is limited, and further studies are warranted.     

Clinical trials in spontaneous disease in dogs: a new paradigm for investigations of sepsis

Objective: To provide evidence that naturally occurring sepsis in dogs provides a unique opportunity to test new therapies in clinically relevant settings. Data sources: Human and veterinary literature. Human data synthesis: Sepsis is a devastating condition responsible for most intensive care unit deaths. Most clinical trials targeting inflammatory mediators of sepsis have failed to improve outcome in clinical patients despite promising results in laboratory animal models. Animal models of sepsis fail to reproduce the clinical syndrome and therefore lead to conclusions that may not be relevant to clinical care. Veterinary data synthesis: Sepsis is recognized but not well‐characterized in companion animal species. Despite some species variability, the cardiopulmonary response to sepsis in dogs is similar to humans. Additionally, inflammatory and coagulation changes that accompany canine sepsis are consistent with those documented in humans. Sepsis secondary to canine parvoviral infection offers the advantages of relative population homogeneity, predictable course, and easy early diagnosis. The disadvantages of canine parvovirus are that it affects a predominantly young and healthy population and results in low mortality with aggressive supportive care. Septic peritonitis and pneumonia have high mortality but can be challenging to diagnose, have a variable course, and affect a heterogeneous population, which can be an advantage or a disadvantage. Conclusions: Similar to trials currently being performed in canine cancer patients, veterinary clinical trials of new sepsis therapeutics may provide a unique opportunity to advance the treatment of sepsis in dogs, humans, and other species. Spontaneous sepsis from canine parvovirus, peritonitis, and pneumonia are common clinical conditions in which therapeutics can be tested.