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Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction
The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.
Journal Article
Australia's Response to COVID-19
Australia suffered two waves of the coronavirus disease 2019 pandemic in 2020: the first lasting from February to July 2020 was mainly caused by transmission from international arrivals, the second lasting from July to November was caused by breaches of hotel quarantine which allowed spreading into the community. From a second wave peak in early August of over 700 new cases a day, by November 2020 Australia had effectively eliminated community transmission. Effective elimination was largely maintained in the first half of 2021 using snap lockdowns, while a slow vaccination programme left Australia lagging behind comparable countries. This paper describes the interventions which led to Australia's relative success up to July 2021, and also some of the failures along the way.
Journal Article
Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies
Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.
Journal Article
Measles and Rubella Elimination in the Western Pacific Region in 2013–2022: Lessons Learned from Progress and Achievements Made during Regional and Global Measles Resurgences
Measles is the most contagious communicable disease, causing an estimated 5.5 million cases and more than 30,000 deaths in the Western Pacific Region (WPR) during 2000. Rubella infection in a pregnant woman can be devastating for the foetus, resulting in congenital rubella syndrome (CRS) in 90% of rubella infections in early pregnancy. It was estimated that approximately 9000 CRS cases occurred in the WPR in 2010. World Health Organization (WHO) Member States in the WPR decided in 2003 to eliminate measles and in 2014 to eliminate rubella from the region. While the WPR successfully attained historically low measles incidence in 2012, it experienced a region-wide measles resurgence in 2013–2016. During the regional resurgence, WHO and Member States accumulated greater knowledge on the epidemiology of measles and rubella in the WPR and strategies to maintain gains. The implementation of the resulting new regional strategy and plan of action from 2018 has proven that measles and rubella elimination is achievable and sustainable under the pressure of multiple importations of measles virus during the world-wide measles resurgences in 2018–2019. This article discusses this progress and achievements towards achieving the global eradication of measles and rubella.
Journal Article
Population Pharmacokinetics of Therapeutic Monoclonal Antibodies
A growing number of population pharmacokinetic analyses of therapeutic monoclonal antibodies (mAbs) have been published in the scientific literature. The aims of this article are to summarize the findings from these studies and to relate the findings to the general pharmacokinetic and structural characteristics of therapeutic mAbs. A two-compartment model was used in the majority of the population analyses to describe the disposition of the mAb. Population estimates of the volumes of distribution in the central (V
1
) and peripheral (V
2
) compartments were typically small, with median (range) values of 3.1 (2.4–5.5) L and 2.8 (1.3–6.8) L, respectively. The estimated between-subject variability in the V
1
was usually moderate, with a median (range) coefficient of variation (CV) of 26% (12–84%). Between-subject variability in other distribution-related parameters such as the V
2
and intercompartmental clearance were often not estimated. Although the pharmacokinetic models used most frequently in the population analyses were models with linear clearance, other models with nonlinear, or parallel linear and nonlinear clearance pathways were also applied, as many therapeutic mAbs are eliminated via saturable target-mediated mechanisms. Population estimates of the maximum elimination rate (V
max
) and the mAb concentration at which elimination was at half maximum for Michaelis-Menten-type elimination pathways varied considerably among the different therapeutic mAbs. However, estimates of the total clearance (CL) of mAbs with linear clearance characteristics and of the clearance of mAbs via the linear clearance pathway (CL
L
) with parallel linear and nonlinear clearance were quite similar for the different mAbs and typically ranged from 0.2 to 0.5 L/day, which is relatively close to the estimated clearance of endogenous IgG of 0.21 L/day. The between-subject variability in the V
max
, CL and CL
L
was moderate to high, with estimated CVs ranging from 15% to 65%. Measures of body size were the covariates most commonly identified as influencing the pharmacokinetics of therapeutic mAbs.
In summary, many features of the population pharmacokinetics of currently used therapeutic mAbs are similar, despite differences in their pharmacological targets and studied patient populations.
Journal Article
On Democratic Backsliding
Democratic backsliding (meaning the state-led debilitation or elimination of the political institutions sustaining an existing democracy) has changed dramatically since the Cold War. Open-ended coups d’état, executive coups, and blatant election-day vote fraud are declining while promissory coups, executive aggrandizement and strategic electoral manipulation and harassment are increasing. Contemporary forms of backsliding are especially vexing because they are legitimated by the very institutions democracy promoters prioritize but, overall, backsliding today reflects democracy’s advance and not its retreat. The current mix of backsliding is more easily reversible than the past mix and successor dictatorships are shorter-lived and less authoritarian.
Journal Article