Current Clinical Pharmacology - Volume 2, Issue 1, 2007

Nearly 20% of all pregnancies end in early pregnancy failure, and surgical evacuation of retained products of conception is often used to manage this failure. Misoprostol is an inexpensive, stable analog of prostaglandin E1, and is powerful at contracting the uterus. With intravaginal misoprostol, the peak plasma levels are lower, but the levels after 4 hours are higher, than after oral or sublingual administration. With oral misoprostol, the evacuation rates in early pregnancy varied from about 50% up to 96%. Similar variation in evacuation rates were obtained from small trials with intravaginal misoprostol. To date, only small studies have used sublingual misoprostol, and there has been no direct comparison to oral or intravaginal misoprostol. A recent large clinical trial has shown, that with intravaginal misoprostol 800 μg, an expulsion rate of 84% can be achieved by 8 days. This large trial also established that women prefer misoprostol to surgical evacuation. Two economic evaluations have shown that misoprostol treatment is less costly than surgical intervention. On the basis of recent findings, it seems likely that misoprostol treatment will become a standard or preferred treatment for early pregnancy failure.

Due to its narrow therapeutic index and substantial inter-patient variability in clinical response, warfarin represents an ideal drug candidate to benefit from the promise of pharmacogenomic-guided dosing strategies. Consistent with in vitro data, clinical studies have demonstrated that CYP2C9 polymorphisms significantly influence warfarin pharmacokinetics by reducing (S)-warfarin metabolic clearance, consequently lowering maintenance dose requirements and increasing the risk over-anticoagulation during the initiation phase of therapy. Recent data suggest that polymorphisms in genes encoding several pharmacodynamic determinants of the coagulation cascade may also influence warfarin's antithrombotic dose-response. Of these, VKORC1 polymorphisms account for a significant proportion of the inter-individual variability in warfarin dose requirements in all populations evaluated. Collectively, these data suggest that assessment of genetic polymorphisms affecting both warfarin pharmacokinetics and pharmacodynamics could help to predict warfarin dose requirements in patients. Therefore, the promise of pharmacogenomic-guided dosing as a useful strategy to improve clinical outcomes with warfarin therapy appears credible and warrants further investigation.

Clinical pharmacology intends to predict drug-specific effects and side effects based on pharmacokinetics (i.e. absorption, distribution, metabolism and elimination) and pharmacodynamics (i.e. dose/effect relationship). Developmental pharmacology focuses on the maturational aspects of these phenomena during perinatal life and later stages of infancy. In general, phenotypic variation in drug metabolism is based on constitutional, environmental and genetic factors but in early neonatal life, it mainly reflects ontogeny. Although the major site of drug metabolism is the liver, the gastrointestinal tract, blood cells and other organs like kidneys or lungs might also be involved in drug metabolism. Important alterations in hepatic drug metabolism occur in early neonatal life. These alterations are of relevance when agedependent aspects of pharmacokinetics, -dynamics or toxicology are considered. Age dependent maturation of various phase I and II processes will be illustrated based on recently reported observations on the in vivo disposition of various analgesics (paracetamol, tramadol) in human neonates and young infants. However, age only in part explains the interindividual variability observed. Therefore, concerted efforts should be developed to simultaneously assess the impact of age, environmental factors, comorbidity and polymorphisms in this specific population. The implementation of multivariable models like non-linear mixed effects (NONMEM) models hereby provide us with the tools to disentangle the impact of various co-variables in this specific population.

The majority of drugs approved for the treatment of malignant disease are traditional cytotoxic agents that, in many cases, have been in use for decades. In the recent past, we have seen the approval of the so-called targeted agents and with this have emerge concepts such as biomarker and optimal biological dose, but which came first and what is actually behind the paradigm shift that is all too evident in modern oncology drug development? Following critical examination of the issue, it can be argued that many, if not all, cytotoxic chemotherapies are targeted, for example, methotrexate, the folate pathway and the use of neutropenia as a biomarker although not titled as such, in the development of these agents. The most obvious change is the toxicity profile of the new molecular entities and, therefore, the recognition that driving a dose towards a maximally tolerated dose for use in later phase development is inappropriate. Again, it can be argued that this should never have been appropriate, however, the tools necessary to determine the underlying pharmacokinetic/pharmacodynamic (PK/PD) relationships were lacking. We believe this has brought about the most dramatic change in how oncology drugs are developed, rather than the classification as cytotoxic or targeted. We will argue that it is not practicable to develop a targeted agent using the traditional paradigm, but equally, the same would now be true for cytotoxics.

Systemic fungal infections are a major threaten for immunocompromised patients. Beside the antimycotic spectrum, the pharmacokinetic properties of an antifungal drug are crucial for its clinical efficacy. Since patients with systemic mycoses frequently present with a significant co-morbidity, pharmacokinetics under special conditions such as renal insufficiency, renal replacement therapy or impaired liver function have to be considered. Amphotericin B is eliminated unchanged by the liver and the kidney. Its plasma protein binding accounts for 95 to 99 percent. Conventional amphotericin B deoxycholate has a remarkable infusion related and renal toxicity. Therefore, lipid formulations have been developed. By now, three lipid formulations are therapeutically used: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. Striking differences in their plasma pharmacokinetics have been found. These differences can be attributed to the diverse disposition of the lipid moieties, while liberated amphotericin B displays a pharmacokinetic behavior which is independent from the lipid-formulation applied. The highest amphotericin B tissue concentrations have been found in the liver and in the spleen, followed by lung, kidney and heart. Concentrations in brain tissue are very low. Flucytosine has no relevant protein binding and is eliminated by glomerular filtration. Fluconazole, itraconazole, voriconazole, posaconazole and ravuconazole are triazoles, used for treatment of systemic fungal infections. Significant drug interactions have to be considered during therapy with triazoles, particularly in patients dependent on immunosuppression. These interactions are caused by the metabolism of triazoles in the liver where the cytochrome P450 (CYP) system is involved at a different extend as well as by their mechanisms of action. Triazoles display a favorable tissue distribution with high penetration into the central nervous system. Echinocandins such as caspofungin and micafungin are rapidly taken up by peripheral tissues, particularly by the liver. In the first 24 hours this uptake appears to be the main route of elimination from plasma. Enzymatic degradation takes place, but is independent of CYP. Thus, drug interactions are a minor problem during echinocandin treatment. The highest tissue levels of caspofungin and micafungin have been measured in the liver. Moderate concentrations are achieved in lung, spleen and kidney. Penetration into the brain is relatively poor.

Malaria is an important problem of public health. It is estimated that 350 to 500 million clinical cases occur annually, which cause 1.1 and 1.3 million deaths every year. The excessive activation of the immune system plays an important role in the pathogenesis of the disease. The cells of the immune system of Plasmodium-infected individuals not only produce large amounts of cytokines, which have anti-parasite effects, but also participate in the pathogenesis of the severe complications of malaria. A central feature of P. falciparum infection is the sequestration of parasitized erythrocytes within the small vessels of major organs. This involves molecular interactions between antigens of parasitized erythrocytes and host receptors, expressed on the surface of endothelial cells. The increased production of pro-inflammatory cytokines and nitric oxide, followed by the up regulation of endothelial cell adhesion molecules, influences the progression of cerebral lesions. The association of drugs capable of modulating the immune response to anti plasmodial drugs has been evaluated. Antibodies to tumor necrosis factor, pentoxifylline, and thalidomide have been tried for this purpose with variable success. This review submitted this subject to a critical assessment and suggests ways to take advantage of immunomodulatory drugs, associated to anti parasite therapy, to reduce the morbimortality of malaria.

Busulphan (Bu) is an alkylating agent that, when combined with agents such as cyclophosphamide (Cy), ablates the bone marrow prior to blood or marrow transplantation. There is wide inter- and intra- patient variability in Bu pharmacokinetics. Early pharmacodynamic studies suggested a significant relationship between high Bu exposure and the occurrence of veno-occlusive disease of the liver, but were not performed in uniform patient populations and tended to use a Cy dose of 200mg/kg. Pharmacodynamic studies in uniform patient populations, with lower doses of Cy, contradict these results. Despite 20 years of clinical use, pharmacodynamic studies are still required to define the relationship between Bu exposure and optimal transplant outcome, and these may vary according to age, disease, transplant type and conditioning regimen. Given the availability now of an intravenous formulation, it is timely to review how and why we are giving Bu. Administration of single daily doses of Bu has been shown to be safe and effective with oral Bu and has been used with i.v. preparations. This simple administration provides accuracy in measuring exposure, which is ideal for pharmacokinetic studies, and provides the possibility of defining a target exposure level associated with a good outcome. Only when this target is defined will therapeutic drug monitoring be useful to minimise toxicity, maximise efficacy and improve transplant outcome.

CYP2C9 and CYP2C19 are important drug metabolizing enzymes and together metabolize about 18% of currently available drugs. Some of the important groups of drugs that are metabolized by them are antihypertensives, hypoglycemics, anticonvulsants, antiulcer drugs etc. Genes encoding these enzymes are polymorphically expressed. Thirty variant alleles for CYP2C9 and 21 for CYP2C19 have been reported. The frequencies of these polymorphic alleles show marked inter-ethnic variation. Several reports have been published showing the clinical importance of this polymorphism. This review summarizes the currently available important information on this topic.