Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management.

BACKGROUND: Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm. OBJECTIVE: To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA). METHODS: We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1  June 2018 to 31  June 2020. Using ICD-10 coding, folders of adults ≥18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event. RESULTS: A total of 142 acute angioedema episodes were included, with a median (interquartile range) age of 42 (28 - 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20 (14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care. CONCLUSION: Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

Self-reported beta-lactam allergy in government and private hospitals in Cape Town, South Africa.

BACKGROUND: Up to a quarter of inpatients in high-income countries (HICs) self-report beta-lactam allergy (BLA), which if incorrect,increases the use of alternative antibiotics, worsening individual health outcomes and driving bacterial resistance. In HICs, up to 95% ofself-reported BLAs are incorrect. The epidemiology of BLA in low- and middle-income African countries is unknown. OBJECTIVES: To describe the epidemiology and de-labelling outcomes of self-reported BLA in hospitalised South African (SA) patients. METHODS: Point-prevalence surveys were conducted at seven hospitals (adult, paediatric, government and privately funded, district andtertiary level) in Cape Town, SA, between April 2019 and June 2021. Ward prescription records and in-person interviews were conductedto identify and risk-stratify BLA patients using the validated PEN-FAST tool. De-labelling was attempted at the tertiary allergy clinic atGroote Schuur Hospital. RESULTS: A total of 1 486 hospital inpatients were surveyed (1 166 adults and 320 children). Only 48 patients (3.2%) self-reported a BLA,with a higher rate in private than in government-funded hospitals (6.3% v. 2.8%; p=0.014). Using the PEN-FAST tool, only 10.4% (n=5/48)of self-reported BLA patients were classified as high risk for true penicillin hypersensitivity. Antibiotics were prescribed to 70.8% (n=34/48)of self-reported BLA patients, with 64.7% (n=22/34) receiving a beta-lactam. Despite three attempts to contact patients for de-labelling atthe allergy clinic, only 3/36 underwent in vivo testing, with no positive results, and 1 patient proceeded to a negative oral challenge. CONCLUSION: Unlike HICs, self-reported BLA is low among inpatients in SA. The majority of those who self-reported BLA were low risk fortype 1 hypersensitivity, but outpatient de-labelling efforts were largely unsuccessful.

Auricular prosthesis positioning using virtual planning in combination with additive manufacturing.

INTRODUCTION: This study focused on deformed or missing auricles and their replacement with silicone prostheses which are retained by craniofacial implants. Surgeons find it difficult to accurately place the implants in relation to the missing auricle in theatre. The aim of this study was to develop patient-specific devices using additive manufacturing technologies and associated software to indicate the positions of implants and to correctly orientate the prostheses relative to the positions of the implants. MATERIAL AND METHODS: The morphology of the patient was determined using Computed-Tomography (CT) scanning and the opposite auricle was mirrored in the virtual environment through specialized software from Materialise. A positioning guide for placing the implants was developed, together with an orientation guide that orientates the prosthesis accurately in relation to the implants. The orientation guide is a new development in the field of maxillofacial prosthetics and has not been attempted before. The guides are produced in nylon through laser sintering additive manufacturing. RESULTS: The accuracy of implant placements was determined and the results showed relatively accurate positioning using the guides. DISCUSSION: Implant placement showed some deviation which can largely be attributed to improper use of the guide by the surgeon during the marking of implant positions. The orientation guide can however somewhat compensate for this to still achieve aesthetically pleasing results. Using the guides significantly reduces risk, time and cost in placing the implants and producing auricular silicone prostheses.

LSD and psilocybin for chronic nociplastic pain: A narrative review of the literature supporting the use of classic psychedelic agents in chronic pain.

Healthcare providers face the challenging task of managing patients who suffer from chronic nociplastic pain conditions. Pain is a multidimensional experience, and the current approach to managing people in chronic pain often fails to meet the needs of these patients. Novel ways of treating people who suffer from chronic nociplastic pain with classic psychedelic agents may offer a new lens through which to approach their pain. Lysergic acid diethylamide (LSD) and psilocybin are both serotonergic agents with a long history of use in treating people with chronic pain and mental health disorders. The new wave of research into psychedelics for major depressive disorder provides an opportunity to investigate and understand the potential for incorporating these drugs into chronic pain management pathways. This narrative review presents healthcare workers with a framework to understand the method of action of these drugs in chronic nociplastic pain pathways and a brief history into their use. We conducted an online search using Pubmed with keywords 'chronic pain' AND/OR 'psilocybin' AND/OR 'lysergic acid diethylamide' AND/OR 'psychedelics' with no date limit applied. We identified further articles that contained information on the neuroscience of psychedelics and the serotonergic system using Google Scholar. During the final stages of writing the article, the latest publications on psychedelics and chronic pain in leading pain journals were again included to update the information.

Topical treatment of psoriasis: questionnaire results on topical therapy as long-term continuous treatment and use on specific body sites.

BACKGROUND: Currently, no formalized international consensus guidelines exist to direct optimal topical treatment including long-term treatment. OBJECTIVE: In this survey, we aim to examine if and which topicals are used in clinical practice in long-term continuous treatment of psoriasis and how topicals are used in treating specific sites of the body. METHODS: A questionnaire was distributed electronically to dermatologists from the International Psoriasis Council (IPC) representing 26 countries. RESULTS: The top three topicals used across all severities of disease were topical corticosteroids, vitamin D analogs, and potent topical corticosteroids in combination with vitamin D analogs. On locations where the skin is thin, flexural and genital psoriasis, lower potency topical corticosteroids were used, whereas on other sites, in particular in palmoplantar psoriasis, superpotent topical corticosteroids and combination vitamin D analogs/corticosteroids were used. CONCLUSIONS: It is relevant to optimize localized therapy for all severities of psoriasis reconciling disease activity (stable vs. unstable disease), localization of the lesions and the individual patient and his/her perspectives on disease control. Topical therapies are valuable treatments for classical mild disease and may have a position in some patients with more severe manifestations.

Psoriasis severity: commonly used clinical thresholds may not adequately convey patient impact.

BACKGROUND: Psoriasis severity is usually evaluated using quantitative and qualitative measures, including per cent body surface area (BSA) involvement, the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI), a patient-reported questionnaire. However, standardized definitions for psoriasis severity categories have not been well established. A PASI of 10 or 12 has remained the minimal severity threshold defining eligibility for psoriasis treatments. In the present study, the validity of this cut-off was re-evaluated in the context of quality of life. OBJECTIVE: To determine whether the thresholds commonly used to define moderate psoriasis (PASI of 10-12 and BSA of 10) are supported by patient-reported DLQI data. METHODS: A systematic review of randomized controlled trials that enrolled mild or moderate patients published between January 2000 and June 2017 was used to assess correlations between provider and patient-generated severity at baseline. RESULTS: For subject groups with high impact on quality of life (DLQI > 10), the mean weighted BSA was 7.6 (Range: 7.1-8.4) and the mean weighted DLQI was 11 (Range: 10.2-12.2). Similarly, the mean weighted PASI for patients with DLQI > 10 was 8.7 (Range: 7.1-10.1) and the mean weighted DLQI was 10.9 (Range: 10.1-12.2). CONCLUSION: Patients with PASI or BSA scores less than 10 can have major quality of life impairment. In general, the objective measures of BSA and PASI alone, when excluding DLQI, may not fully capture the impact of disease severity.

A multicentre, cross-sectional study investigating the prevalence of hypertensive disease in patients presenting for elective surgery in the Western Cape Province, South Africa.

BACKGROUND: Hypertension is common, affecting over one billion people worldwide. In sub-Saharan Africa, hypertensive disease not only affects the older population but is becoming increasingly prevalent in younger individuals. In South Africa (SA), >30% of the adult population has hypertension, making it the single most common cardiovascular risk factor and the predominant contributor to cardiovascular disease and mortality. Elevated blood pressure is the most common perioperative comorbidity encountered in non-cardiac surgical patients, with an overall prevalence of 20 - 25%, and it remains poorly controlled in low- and middle-income countries. Hypertension in the perioperative setting may adversely affect patient outcome. It therefore not only flags possible perioperative challenges to anaesthesiologists, but also identifies patients at risk of long-term morbidity and mortality. OBJECTIVES: To determine the prevalence and severity of hypertension in elective adult surgical patients in the Western Cape Province, SA. RESULTS: The study population included all elective surgical patients from seven hospitals in the Western Cape during a 1-week period. Hypertension, defined as having had a previous diagnosis of hypertension or meeting the blood pressure criteria of >140/90 mmHg, was identified in 51.8% of patients during preoperative assessment. Significantly, newly diagnosed hypertension was present in 9.9% of all patients presenting for elective surgery. Although 98.1% of the known hypertensive patients were on antihypertensive therapy, 36.9% were inadequately controlled. There are numerous reasons for this, but notably 32.1% of patients admitted to forgetting to take their medication, making patient factors the most common reason for treatment non-compliance. CONCLUSIONS: The perioperative period may be an important opportunity to identify undiagnosed hypertensive patients. The perioperative encounter may have a significant public health implication in facilitating appropriate referral and treatment of patients with hypertension to decrease long-term cardiovascular complications in SA.

Optimising perioperative care for hip and knee arthroplasty in South Africa: a Delphi consensus study.

BACKGROUND: A structured approach to perioperative patient management based on an enhanced recovery pathway protocol facilitates early recovery and reduces morbidity in high income countries. However, in low- and middle-income countries (LMICs), the feasibility of implementing enhanced recovery pathways and its influence on patient outcomes is scarcely investigated. To inform similar practice in LMICs for total hip and knee arthroplasty, it is necessary to identify potential factors for inclusion in such a programme, appropriate for LMICs. METHODS: Applying a Delphi method, 33 stakeholders (13 arthroplasty surgeons, 12 anaesthetists and 8 physiotherapists) from 10 state hospitals representing 4 South African provinces identified and prioritised i) risk factors associated with poor outcomes, ii) perioperative interventions to improve outcomes and iii) patient and clinical outcomes necessary to benchmark practice for patients scheduled for primary elective unilateral total hip and knee arthroplasty. RESULTS: Thirty of the thirty-three stakeholders completed the 3 months Delphi study. The first round yielded i) 36 suggestions to preoperative risk factors, ii) 14 (preoperative), 18 (intraoperative) and 23 (postoperative) suggestions to best practices for perioperative interventions to improve outcomes and iii) 25 suggestions to important postsurgical outcomes. These items were prioritised by the group in the consecutive rounds and consensus was reached for the top ten priorities for each category. CONCLUSION: The consensus derived risk factors, perioperative interventions and important outcomes will inform the development of a structured, perioperative multidisciplinary enhanced patient care protocol for total hip and knee arthroplasty. It is anticipated that this study will provide the construct necessary for developing pragmatic enhanced care pathways aimed at improving patient outcomes after arthroplasty in LMICs.

The relationship between pre-operative hypertension and intra-operative haemodynamic changes known to be associated with postoperative morbidity.

Hypertension is not consistently associated with postoperative cardiovascular morbidity and is therefore not considered a major peri-operative risk factor. However, hypertension may predispose to peri-operative haemodynamic changes known to be associated with peri-operative morbidity and mortality, such as intra-operative hypotension and tachycardia. The objective of this study was to determine whether pre-operative hypertension was independently associated with haemodynamic changes known to be associated with adverse peri-operative outcomes. We performed a five-day multicentre, prospective, observational cohort study which included all adult inpatients undergoing elective, non-cardiac, non-obstetric surgery. We recruited 343 patients of whom 164 (47.8%) were hypertensive. An intra-operative mean arterial pressure of < 55 mmHg occurred in 59 (18.2%) patients, of which 25 (42.4%) were hypertensive. Intra-operative tachycardia (heart rate> 100 beats.min-1 ) occurred in 126 (38.9%) patients, of whom 61 (48.4%) were hypertensive. Multivariable logistic regression did not show an independent association between the stage of hypertension and either clinically significant hypotension or tachycardia, when controlled for ASA physical status, functional status, major surgery, duration of surgery or blood transfusion. There was no association between pre-operative hypertension and peri-operative haemodynamic changes known to be associated with major morbidity and mortality. These data, therefore, support the recommendation of the Joint Guidelines of the Association of Anaesthetists of Great Britain and Ireland (AAGBI) and the British Hypertension Society to proceed with elective surgery if a patient's blood pressure is < 180/110 mmHg.

Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice.

The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of 'big data' should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies.

The global state of psoriasis disease epidemiology: a workshop report.

The International Psoriasis Council, a global nonprofit organization dedicated to innovation across the full spectrum of psoriasis, led a symposium to discuss the current state of psoriasis epidemiology and to introduce the vision and development of a Global Psoriasis Atlas. The symposium was held on 9 September 2015 at the 45th annual meeting of the European Society for Dermatological Research, Rotterdam, the Netherlands. Collectively, these presentations highlighted challenges associated with assessing psoriasis epidemiology and emphasized the urgent need for an authoritative resource to clarify psoriasis disease burden on a global scale.

Topical treatment of psoriasis: questionnaire results on topical therapy accessibility and influence of body surface area on usage.

BACKGROUND: Topical treatment of mild to moderate psoriasis is first-line treatment and exhibits varying degrees of success across patient groups. Key factors influencing treatment success are physician topical treatment choice (high efficacy, low adverse events) and strict patient adherence. Currently, no formalized, international consensus guidelines exist to direct optimal topical treatment, although many countries have national guidelines. OBJECTIVE: To describe and analyse cross-regional variations in the use and access of psoriasis topical therapies. METHODS: The study was conducted as an observational cross-sectional study. A survey was distributed to dermatologists from the International Psoriasis Council (IPC) to assess topical therapy accessibility in 26 countries and to understand how body surface area (BSA) categories guide clinical decisions on topical use. RESULTS: Variation in the availability of tars, topical retinoids, dithranol and balneotherapy was reported. The vast majority of respondents (100% and 88.4%) used topical therapy as first-line monotherapy in situations with BSA < 3% and BSA between 3% and 10%, respectively. However, with disease severity increasing to BSA > 10%, the number of respondents who prescribe topical therapy decreased considerably. In addition, combination therapy of a topical drug and a systemic drug was frequently reported when BSA measured >10%. CONCLUSION: This physician survey provides new evidence on topical access and the influence of disease severity on topical usage in an effort to improve treatment strategies on a global level.

Biosimilars for psoriasis: clinical studies to determine similarity.

Biosimilars are drugs that are similar, but not identical, to originator biologics. Preclinical analytical studies are required to show similarity on a molecular and structural level, but efficacy and safety studies in humans are essential to determining biosimilarity. In this review, written by members of the International Psoriasis Council, we discuss how biosimilars are evaluated in a clinical setting, with emphasis on extrapolation of indication, interchangeability and optimal clinical trial design.

Salivary Cortisol and Cortisone do not Appear to be Useful Biomarkers for Monitoring Hydrocortisone Replacement in Addison's Disease.

Salivary cortisol has been used to monitor hydrocortisone replacement in patients with Addison's disease (AD). Since salivary cortisol is metabolised to salivary cortisone, it may be an adjunctive analyte to assess adequacy of hydrocortisone replacement in patients with AD. We aimed to characterise the exposure of salivary cortisol and cortisone in patients and healthy controls. We measured salivary cortisol and cortisone by liquid chromatography-tandem mass spectrometry and constructed a day curve (08:00 until 24:00 h) with 16 time points in 25 AD patients taking their usual hydrocortisone dose and in 26 healthy controls. The median (interquartile range) area under the curve (AUC) for cortisol was not different for patients, compared with controls [55.63 (32.91-151.07) nmol*min*l-1 vs. 37.49 (27.41-52.00) nmol*min*l-1; p=0.098, respectively], whereas the peak cortisol Cmax was higher in patients [32.61 (5.75-146.19) nmol/l vs. 8.96 (6.96-12.23) nmol/l; p=0.013], compared with controls. The AUC for cortisone [23.65 (6.10-54.76) nmol*min*l-1 vs. 227.73 (200.10-280.52) nmol*min*l-1; p≤ 0.001, respectively], and peak cortisone Cmax was lower in patients than in controls [11.11 (2.91-35.85) nmol/l vs. 33.12 (25.97-39.95) nmol/l; p=0.002]. The AUC for salivary cortisol and salivary cortisone were not correlated with any measures of hydrocortisone dose. The time-course and AUC of salivary cortisol were similar between Addison's patients and healthy controls. Patients had substantially lower salivary cortisone AUC, compared to healthy controls. Salivary cortisol AUC and pharmacokinetics were not related to hydrocortisone dose and thus are not likely useful markers for the adequacy of hydrocortisone replacement.

Identification of key research needs for topical therapy treatment of psoriasis - a consensus paper by the International Psoriasis Council.

In this age of expanding choices of therapy for psoriasis, topical therapies still play an important part in the management of patients. There are many knowledge gaps in topical therapy for psoriasis with regard to efficacy and safety as well as various combinations including topical therapy with phototherapy or with systemic agents. Councillors of the International Psoriasis Council comprised a topical therapy working group to describe these gaps in order to help direct future research endeavours. Herein, we present the results of this analysis, discuss topical agents in clinical development and the attributes of the ideal topical treatment for psoriasis.

The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients.

BACKGROUND: Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions. METHODS: An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine. RESULTS: We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 µg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 µg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax. CONCLUSION: Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group. TRIAL REGISTRATION: Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Biosimilars for psoriasis: preclinical analytical assessment to determine similarity.

Biosimilars, sometimes called 'generic biologics', are no longer a vision for the future but a present-day reality. Drug manufacturers and regulatory authorities are charged with ensuring that these products are safe and effective. Because biologically produced medications are large, complex proteins, many factors affect the quality of the end product, including glycosylation and presence of impurities, and thus many factors need to be compared between an emerging biosimilar and its originator biologic. Indeed, preclinical analytical assessments to determine similarity to an originator biologic are critical and are considered to be the foundation for regulatory approval of biosimilars. Here, the science behind the preclinical development of biosimilars is discussed by members of the International Psoriasis Council, and suggestions are put forth to try to ensure that future biosimilars are produced in a high quality and standardized manner.

The pharmacokinetics of lopinavir/ritonavir when given with isoniazid in South African HIV-infected individuals.

Isoniazid preventive therapy is recommended in patients on antiretroviral treatment (ART) with latent tuberculous infection to prevent progression to active tuberculosis disease. Isoniazid (INH) inhibits cytochrome (CY) P3A4, which metabolises lopinavir (LPV). The administration of INH may cause higher LPV concentrations, which may increase LPV toxicity. LPV bioavailability is increased by co-formulated ritonavir (r), which may enhance the interaction of INH on LPV. We studied the effect of INH on LPV concentrations by administering INH for 7 days and performing intensive pharmacokinetic sampling in 16 human immunodeficiency virus infected patients established on LPV/r-based ART. INH did not significantly increase steady-state LPV area under the plasma concentration-time curve calculated for the 12 h-dosing interval.

A Nonlinear Mixed Effects Pharmacokinetic Model for Dapagliflozin and Dapagliflozin 3-O-glucuronide in Renal or Hepatic Impairment.

Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40-55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e42; doi:10.1038/psp.2013.20; advance online publication 8 May 2013.

The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals.

Isoniazid preventive therapy (IPT) is recommended in patients on antiretroviral treatment. Isoniazid (INH) inhibits CYP3A4, which metabolises nevirapine (NVP). Administration of INH may cause higher NVP concentrations and toxicity. We studied the effect of INH on NVP concentrations in 21 patients randomised to either placebo (n = 13) or INH (n = 8) in an ongoing trial of IPT in patients on ART. INH was associated with a 24% increase in median NVP area under the plasma concentration-time curve for the 12 h dosing interval, which was not statistically significant (P = 0.66).