Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility.

BACKGROUND: Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment. RESULTS: Atropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 µg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols. CONCLUSIONS: Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 µg/kg/24 h offers a safe alternative.

Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.

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.

Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle?

Atazanavir and darunavir total concentrations (drug bound to plasma proteins plus unbound drug) progressively decrease during pregnancy. This pharmacokinetic variation leads physicians to recommend increasing doses. Conversely, the unbound concentration (Cu), i.e. the pharmacologically active form of the drug, remains unchanged. The explanation of this desynchronization lies in the fact that the clearance of the unbound form, corresponding to the intrinsic metabolic capacity of the hepatocytes, is the only factor driving Cu, and is constant during pregnancy. The attention of HIV physicians should be attracted to this aspect of pharmacokinetics, which is often incompletely understood and could lead to inadequate dose adjustment, which could then cause overexposure of the foetus for many months, with unknown consequences.

A large potentiation effect of serum on the in vitro potency of tulathromycin against Mannheimia haemolytica and Pasteurella multocida.

The antimicrobial properties of tulathromycin were investigated for M. haemolytica and P. multocida. Three in vitro indices of antimicrobial activity, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill curves, were established for six isolates of each organism. Each index was measured in two growth media: Mueller-Hinton broth (MHB) and calf serum. It was shown that MICs and MBCs were markedly lower in serum than in MHB. MHB:serum ratios for MIC were 47:1 (M. haemolytica) and 53:1 (P. multocida). For both serum and MHB, adjustment of pH led to greater potency at alkaline compared to acid pH. Tulathromycin MIC was influenced by size of inoculum count, being 4.0- to 7.7-fold greater for high compared to low initial counts. It was concluded that for the purpose of determining dosages for therapeutic use, pharmacodynamic data for tulathromycin should be derived in biological fluids such as serum. It is hypothesized that in vitro measurement of MIC in broth, conducted according to internationally recommended standards, may be misleading as a basis for estimating the in vivo potency of tulathromycin.

Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf.

The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC(0-24 h) /MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts.

Sulfadimethoxine in giant freshwater prawns (Macrobrachium rosenbergii): an attempt to estimate the withdrawal time by a population pharmacokinetic approach.

The fates of sulfadimethoxine (SDM) for different routes of administration were investigated in muscle tissue of giant freshwater prawns, Macrobrachium rosenbergii, following either intramuscular (i.m.) or gavage administration at a dosage of 50 mg/kg body weight (b.w.). The depletion patterns of SDM were also examined after medicated feed treatment at the feeding concentration of 10 g/kg of feed twice a day at a rate of 1% of total b.w. for five consecutive days. The concentration of SDM in prawn muscle tissue was measured using a high-performance liquid chromatography (HPLC) equipped with ultraviolet detector. Noncompartmental analyses were used to estimate basic pharmacokinetic parameters for the i.m. and gavage data, while a population model was developed to analyze the entire data set including the feed group. Using the Monte Carlo simulations, the withdrawal times (WT) for the orally administered SDM in feed supplement were determined. Maximum concentration of SDM was significantly higher in the i.m. than in the gavage group, and the area under the curve (AUC) value for relative bioavailability following gavage administration was 25.6%. Using Monte Carlo simulation, for a maximum residue limit (MRL) of 0.1 µg/g, the WT for muscle after oral administration of SDM in feed was estimated to be 67 h, while for a MRL of 0.2 µg/g, the WT was estimated to be of 54 h.

Pharmacokinetics, pharmacodynamics, toxicology and therapeutics of mavacoxib in the dog: a review.

Mavacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)-2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half-life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half-life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX-1 and COX-2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.

Pharmacokinetic/pharmacodynamic integration and modelling of amoxicillin for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.

The antimicrobial properties of amoxicillin were determined for the bovine respiratory tract pathogens, Mannheima haemolytica and Pasteurella multocida. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill curves were established. Pharmacokinetic (PK)/pharmacodynamic (PD) modelling of the time-kill data, based on the sigmoidal Emax equation, generated parameters for three levels of efficacy, namely bacteriostatic, bactericidal (3log10 reduction) and 4log10 reduction in bacterial counts. For these levels, mean AUC(0-24 h) /MIC serum values for M. haemolytica were 29.1, 57.3 and 71.5 h, respectively, and corresponding values for P. multocida were 28.1, 44.9 and 59.5 h. Amoxicillin PK was determined in calf serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids, after intramuscular administration of a depot formulation at a dosage of 15 mg/kg. Mean residence times were 16.5 (serum), 29.6 (exudate) and 29.0 h (transudate). Based on serum MICs, integration of in vivo PK and in vitro PD data established maximum concentration (Cmax )/MIC ratios of 13.9:1 and 25.2:1, area under concentration-time curve (AUC0-∞ )/MIC ratios of 179 and 325 h and T>MIC of 40.3 and 57.6 h for P. multocida and M. haemolytica, respectively. Monte Carlo simulations for a 90% target attainment rate predicted single dose to achieve bacteriostatic and bactericidal actions over 48 h of 17.7 and 28.3 mg/kg (M. haemolytica) and 17.7 and 34.9 mg/kg (P. multocida).

Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation.

Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three-period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half-life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half-life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivo IC50 COX-1/IC50 COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood.

Workshop report: the 2012 antimicrobial agents in veterinary medicine: exploring the consequences of antimicrobial drug use: a 3-D approach.

Antimicrobial resistance is a global challenge that impacts both human and veterinary health care. The resilience of microbes is reflected in their ability to adapt and survive in spite of our best efforts to constrain their infectious capabilities. As science advances, many of the mechanisms for microbial survival and resistance element transfer have been identified. During the 2012 meeting of Antimicrobial Agents in Veterinary Medicine (AAVM), experts provided insights on such issues as use vs. resistance, the available tools for supporting appropriate drug use, the importance of meeting the therapeutic needs within the domestic animal health care, and the requirements associated with food safety and food security. This report aims to provide a summary of the presentations and discussions occurring during the 2012 AAVM with the goal of stimulating future discussions and enhancing the opportunity to establish creative and sustainable solutions that will guarantee the availability of an effective therapeutic arsenal for veterinary species.

Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis.

The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix®). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5-4 h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg), cefalexin (15 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 min, but ampicillin (20 mg/kg) required 82 min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2 h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill dogs) may cover E. coli contaminations, but only if readministered every 1.5 h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing.

Antimicrobial prophylaxis in companion animal surgery: A scoping review for European Network for Optimization of Antimicrobial Therapy (ENOVAT) guidelines.

Surgical antimicrobial prophylaxis (SAP) is widely used to reduce the risk of surgical site infections (SSI), but there is uncertainty as to what the proportion of SSI reduction is. Therefore, it is difficult for surgeons to properly weigh the costs, risks and benefits for individual patients when deciding on the use of SAP, making it challenging to promote antimicrobial stewardship in primary practice settings. The objective of this study was to map the veterinary evidence focused on assessing the effect of SAP on SSI development and in order to identify surgical procedures with some research evidence and possible knowledge gaps. In October 2021 and December 2022, Scopus, CAB Abstracts, Web of Science Core Collection, Embase and MEDLINE were systematically searched. Double blinded screening of records was performed to identify studies in companion animals that reported on the use of SAP and SSI rates. Comparative data were available from 34 out of 39123 records screened including: eight randomised controlled trials (RCT), 23 cohort studies (seven prospective and 16 retrospective) and three retrospective case series representing 12476 dogs and cats in total. Extracted data described peri- or post-operative SAP in nine, and 25 studies, respectively. In the eight RCTs evaluating SAP in companion animals, surgical procedure coverage was skewed towards orthopaedic stifle surgeries in referral settings and there was large variation in SAP protocols, SSI definitions and follow-up periods. More standardized data collection and agreement of SSI definitions is needed to build stronger evidence for optimized patient care.

The consequences of generic marketing on antibiotic consumption and the spread of microbial resistance: the need for new antibiotics.

In both human and veterinary medicine, it has been shown that flooding the market with different generics and/or 'me-too' branded drugs has increased overall antibiotic consumption correlating with the emergence and spread of bacterial resistance to antibiotics. Another possible undesirable consequence of the promotion of generics is the promotion of an economic incentive that encourages the use of old drug products with very poor oral bioavailability, marketed with historical dosage regimens and extensively excreted in the environment. What veterinary medicine rather needs is new innovative and 'ecofriendly' antibiotics to actually enforce a more prudent use of antibiotics. For a pharmaceutical company, generics are inexpensive to manufacture and on a short-term basis, the generic market is very appealing. However, on a long-term basis, this marketing orientation provides a disincentive to the development of new and innovative products that will be required to meet the therapeutic needs of the veterinary community while being consistent with public health concerns. Indeed, for veterinary medicine, the key issue surrounding antibiotics is public health. It is the opinion of the authors that veterinary antibiotics and/or veterinary drug formulations should be innovative in terms of selectivity (no or minimal impact on the commensal gut flora), biodegradable (with minimal environmental disruption), and more expensive, with a strictly regulated market rather than unselective, cheap, and freely available drugs.

Veterinary pharmacology: history, current status and future prospects.

Veterinary therapeutics, based on the art of Materia Medica, has been practised for countless centuries, but the science of veterinary pharmacology is of very recent origin. This review traces the contribution of Materia Medica to veterinary therapeutics from the Egyptian period through to the Age of Enlightenment. The first tentative steps in the development of the science of veterinary pharmacology were taken in the 18th century, but it was not until the mid 20th century that the science replaced the art of Materia Medica. This review traces the 20th century developments in veterinary pharmacology, with emphasis on the explosion of knowledge in the 35 year period to 2010. The range of factors which have influenced the current status of the discipline are reviewed. Future developments are considered from the perspectives of what might be regarded as desirable and those innovations that might be anticipated. We end with words of encouragement for young colleagues intent upon pursuing a career in veterinary pharmacology.

Animal Health Modeling & Simulation Society: a new society promoting model-based approaches in veterinary pharmacology.

The Animal Health Modeling & Simulation Society (AHM&S) is a newly founded association (2012) that aims to promote the development, application, and dissemination of modeling and simulation techniques in the field of Veterinary Pharmacology and Toxicology. The association is co-chaired by Pr. Johan Gabrielsson (Europe), Pr. Jim Riviere (USA), and secretary Dr. Jonathan Mochel (Switzerland). This short communication aims at presenting the membership, rationale and objectives of this group.

Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination.

Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed.

Establishing bioequivalence of veterinary premixes (Type A medicated articles).

a) Key issues concerning Premix (Type A medicated articles) Bioequivalence evaluations: 1) This is a complex issue concerning both route of administration and formulation. 2) If the animal is not at the bunk/trough, the animal is not self-administering (eating medicated feed), thus there can be no drug absorption. b) Differing opinions among scientists and regulatory authorities/expert bodies regarding: 1) No harmonization on how to design, conduct, and interpret in vivo studies. 2) Applicability of biowaivers to Type A (premix) products. 3) Why are topdress and complete feed considered differently? Are they different formulations or different routes of administration? 4) Single dose vs. multi-dose studies. 5) What is the final formulation? c) What are the next steps: 1) Harmonize current bioequivalence guidelines through the VICH process. 2) Determine the applicability/non-applicability of the Biopharmaceutical Classification System (BCS). 3) Establish the Total Mixed Ration (i.e. formulation) effects. 4) Define the test subject (individual, pen, etc.).

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.

Challenges obtaining a biowaiver for topical veterinary dosage forms.

Obtaining a biowaiver for topical drugs used in veterinary species faces many of the same challenges associated with human topicals. However, the skin of domestic animals varies anatomically and biochemically and experimental approaches to assess bioequivalence (BE) in veterinary species have challenges that are not often encountered with human skin. This is especially the situation with locally acting drugs. The focus of this paper is to address several of the challenges associated with (i) determining the BE of these locally acting drugs and (ii) critically examine the current technological advances that can act as a surrogate for clinical trials.