Use of transdermal drug formulations in the elderly

Transdermal drug delivery systems are pharmaceutical forms designed to administer a drug through the skin to obtain a systemic effect. They ensure a constant rate of drug administration and a prolonged action. Several different types of transdermal delivery devices are available on the market. They are either matrix or reservoir systems and their main current uses are to treat neurological disorders, pain and coronary artery disease, and as hormone replacement therapy.Transdermal drug administration has a number of advantages compared with the oral route: it avoids gastrointestinal absorption and hepatic first-pass metabolism, minimizes adverse effects arising from peak plasma drug concentrations and improves patient compliance. Compared with the parenteral route, transdermal administration entails no risk of infection. For elderly people, who are often polymedicated, transdermal drug delivery can be a good alternative route of administration.Transdermal absorption depends on passive diffusion through the different layers of the skin. As skin undergoes many structural and functional changes with increasing age, it would be useful to know whether these alterations affect the transdermal diffusion of drugs. Studies have shown that age-related changes in hydration and lipidic structure result in an increased barrier function of the stratum corneum only for relatively hydrophilic compounds. In practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals. The need for dose adaptation in elderly patients using transdermal drug delivery systems is therefore not related to differences in skin absorption but rather to age-related cardiovascular, cerebral, hepatic and/or renal compromise, and to ensuing geriatric pharmacokinetic and pharmacodynamic changes.     

Pharmacokinetic and toxicity considerations for the use of anthracyclines in ovarian cancer treatment

INTRODUCTION: Safe and effective treatments are needed for ovarian cancer. While there are many drugs currently available, there has recently been a renewed novel interest in the use of anthracyclines. AREAS COVERED: This review summarizes the available evidence on pharmacokinetic (PK) and toxicology implications of anthracyclines and pegylated liposomal doxorubicin (PLD) in the clinical management of women with epithelial ovarian cancer. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to September 2010. EXPERT OPINION: PLD is a liposomal formulation of doxorubicin (DXR), with a distinct pharmacokinetic profile, characterized by extended circulation time and a reduced clearance and volume of distribution with respect to the free drug. PLD is effective and well tolerated in relapsed ovarian cancer. The toxicity profile of PLD is characterized by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression and decreased cardiotoxicity compared to free DXR. The good response rate, toxicity profile and pharmacokinetic profile of PLD suggest that PLD could be an option in first-line and second-line treatment in ovarian cancer; especially in those who had experienced taxane-induced toxicity or had a poor performance status.     

Pharmacokinetic characterization of controlled-release formulations

The development of controlled-release formulations should be based on a clinico-pharmacological rationale such as increased compliance, reduced side effects and improved efficacy. The pharmacokinetic profile of a controlled-release formulation and its dose regimen should be compared under steady-state conditions with that of an immediate-release formulation or that of another controlled-release formulation. Apart from conventional characteristics such as AUC, tmax and Cmax, alternative characteristics are suggested such as residual concentration at the end of the dose interval, peak-through fluctuation in steady state, plateau time, statistical moments, in vivo input functions and intravenous infusion schemes which mimic the concentration/time profile after oral administration of the controlled-release formulation. The pharmacokinetic steady-state profile should be reproduced with and without food, from day to day, and at various dose levels. The in vitro specification should be based on in vivo requirements for "within-product bioequivalence".     

High throughput screening of transdermal formulations

Purpose. Applications of transdermal drug delivery are limited by low skin permeability. Many chemicals have been used to enhance skin permeability, however, only a handful are actually used in practice. Combinations of chemicals are likely to be more efficient in enhancing skin permeability compared to individual enhancers. However, identification of efficient enhancer combinations is quite challenging because many chemical enhancers interact with each other and with the skin in a complex manner. In the absence of a fundamental knowledge of such interactions, we need to rely on rapid methods to screen various enhancer combinations for their effectiveness. In this paper, we report a novel high throughput (HTP) method that is at least 50-fold more efficient in terms of skin utilization and up to 30-fold more efficient in terms of holdup times than the current methods for formulation screening (Franz diffusion cells). Methods. A high throughput method was developed based on skin conductivity and mannitol penetration into the skin. This method was used to perform at least 100 simultaneous tests per day. Detailed studies were performed using two model enhancers, sodium lauryl sulfate (SLS) and dodecyl pyridinium chloride (DPC). The predictions of the high throughput method were validated using Franz diffusion cells. Results. High throughput screening revealed that mixtures of SLS and DPC are significantly more effective in enhancing transdermal transport compared to each of them alone. Maximum efficiency was observed with near-equimolar mixtures of SLS: DPC. The predictions of the HTP method compared well against those made using Franz diffusion cells. Specifically, the effect of surfactant mixtures on skin conductivity and mannitol permeability measured using Franz cells also showed a maximum at near-equimolar mixtures of SLS: DPC. Conclusions. The novel HTP method allows rapid screening of enhancer formulations for transdermal applications. This method can be used to discover new and effective enhancer mixtures. At the same time, these data may also broaden our understanding of the effect of enhancers on skin permeability.     

Pharmacokinetic considerations as to when to use dried blood spot sampling

In the past few years there has been a large increase in the reporting of the use of dried blood spots (DBS) in drug development. Most of these reports pertain to the technological improvements that have allowed for drug concentration measurements from microliter volumes of sample, issues concerning method development, and exploration of the technique, into other areas such as measurement of macromolecules and metabolite identification. One area that has received less attention and is the subject of this commentary concerns the pharmacokinetic issues that arise from using DBS as opposed to plasma, the mainstay matrix. Measurements of drug concentrations from either plasma or dbs are almost always the sum of bound and unbound drug, but it is the unbound drug in plasma (plasma water) that is the relevant driver of essentially all pharmacokinetic and pharmacodynamic events. Therefore, the critical assumption made is constancy in fraction unbound for plasma, and additionally for blood, constancy of hematocrit and blood cell affinity. Often these assumptions are reasonable and either matrix suffices, but not always. Then the value of one matrix over the other depends on the magnitude of the blood-to-plasma concentration ratio of drug, its clearance and the cause of the deviation from constancy. Additional considerations are the kinetics of distribution within blood and those arising when the objective is assessment or comparison of bioavailability. Most of these issues can be explored and addressed in vitro prior to the main drug development program.     

Pharmacokinetic considerations in the treatment of CNS tumours

Despite aggressive therapy, the majority of primary and metastatic brain tumour patients have a poor prognosis with brief survival periods. This is because of the different pharmacokinetic parameters of systemically administered chemotherapeutic agents between the brain and the rest of the body. Specifically, before systemically administered drugs can distribute into the CNS, they must cross two membrane barriers, the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB). To some extent, these structures function to exclude xenobiotics, such as anticancer drugs, from the brain. An understanding of these unique barriers is essential to predict when and how systemically administered drugs will be transported to the brain. Specifically, factors such as physiological variables (e.g. blood flow), physicochemical properties of the drug (e.g. molecular weight), as well as influx and efflux transporter expression at the BBB and BCB (e.g. adenosine triphosphate-binding cassette transporters) determine what compounds reach the CNS. A large body of preclinical and clinical research exists regarding brain penetration of anticancer agents. In most cases, a surrogate endpoint (i.e. CSF to plasma area under the concentration-time curve [AUC] ratio) is used to describe how effectively agents can be transported into the CNS. Some agents, such as the topoisomerase I inhibitor, topotecan, have high CSF to plasma AUC ratios, making them valid therapeutic options for primary and metastatic brain tumours. In contrast, other agents like the oral tyrosine kinase inhibitor, imatinib, have a low CSF to plasma AUC ratio. Knowledge of these data can have important clinical implications. For example, it is now known that chronic myelogenous leukaemia patients treated with imatinib might need additional CNS prophylaxis. Since most anticancer agents have limited brain penetration, new pharmacological approaches are needed to enhance delivery into the brain. BBB disruption, regional administration of chemotherapy and transporter modulation are all currently being evaluated in an effort to improve therapeutic outcomes. Additionally, since many chemotherapeutic agents are metabolised by the cytochrome P450 3A enzyme system, minimising drug interactions by avoiding concomitant drug therapies that are also metabolised through this system may potentially enhance outcomes. Specifically, the use of non-enzyme-inducing antiepileptic drugs and curtailing nonessential corticosteroid use may have an impact.     

Pharmacokinetic criteria for the evaluation of retard formulations

Summary In vivo criteria are proposed for the assessment of retard formulations. If the pharmacokinetics of the retard formulation tested and of the normal preparation are known, in either plasma or urine, two retard quotients can be defined which define the sustained release. One of the quotients refers to the width (half-value duration) and the other to the height of the plasma concentration time curve of the retard form as compared to the conventional preparation. From these criteria it is possible to draw useful conclusions about thein vivo quality of a retard formulation in an early stage of development of the dosage form. As a practical example the criteria have been applied to Noveril^® 240 tablets (dibenzepin hydrochloride), the retard effect of which has made it possible to reduce the frequency of administration from three times daily to once a day.     

Pharmacokinetic considerations in the treatment of childhood epilepsy

Organogenesis throughout childhood affects almost every aspect of pediatric pharmacotherapy. The antiepileptic drugs (AEDs) are particularly impacted since most elimination rates are diminished for the first 6 months of infancy, but quickly attain and supersede adult values. When children enter a hypermetabolic stage, large doses of AEDs may be necessary to maintain effective serum concentrations. Medication noncompliance is frequently confused as hypermetabolism, since both present with low serum drug concentrations. Amazingly, noncompliance among children with chronic illness approaches a similar incidence to that reported in the adult population. It is obviously important to include this in the differential diagnosis of the etiology of subtherapeutic serum AED concentrations. Maturational differences also affect gastrointestinal drug absorption. Intestinal transit time and absorptive surface area are both diminished in young children. Drug delivery systems suitable in adults may not deliver the total dosage in children. Differences in the composition of body compartments and protein binding can alter the volume of drug distribution and, consequently, serum concentrations. In addition to pathophysiologic changes, there is evidence to suggest differences between a mature and immature brain. These differences include quantitative and qualitative responses to neurotransmitters. Hence, it is understandable why seizure semiology is different in children compared with adults. This constellation of factors contributes to the challenges of caring for children with epilepsy.     

Pharmacokinetic considerations in the eradication of Helicobacter pylori

As Helicobacter pylori plays an important role in the aetiopathogenesis of peptic ulcer, therapeutic strategies aimed at maintaining long term remission have shifted from the control of intragastric pH to targeting H. pylori. According to recent international guidelines the clinical goals--rapid ulcer healing and prevention of relapse--can be best accomplished by combination therapy consisting of an antisecretory drug (proton pump inhibitor or ranitidine) and 2 antimicrobial agents (preferable amoxicillin, clarithromycin or metronidazole). When applying such multidrug regimens, possible synergy between the agents suggests that pharmacokinetic considerations might help to improve H. pylori eradication rates, which should be above 85 to 90% on an intention-to-treat basis. The present review summarises the pharmacokinetic properties and interaction potential of all drugs presently used in the various H. pylori eradication regimens, with emphasis on particular patient populations such as the elderly and those with renal impairment. The drugs considered are omeprazole, lansoprazole, pantoprazole, rabeprazole, ranitidine and ranitidine bismutrex, bismuth salts, amoxicillin, clarithromycin, azithromycin, roxithromycin, metronidazole, tinidazole and tetracycline. When addressing the clinically important questions of the efficacy, safety and costs of the recommended regimens, the impact of drug disposition on H. pylori eradication should not be neglected.     

布洛芬离子导入凝胶剂在家兔体内的药动学

目的:通过研究布洛芬凝胶剂的药动学,为布洛芬离子电导入经皮给药系统的临床应用提供理论依据.方法:采用反相高效液相色谱法测定布洛芬凝胶剂透皮给药后不同时间家兔血药浓度,计算药动学参数.结果:布洛芬离子导入凝胶剂的吸收速度、峰浓度及血药浓度时间曲线下面积虽低于离子导入溶液剂,但AUC及C max 分别为透皮给药对照组的 2.6 倍和 4.5 倍,且吸收速度快.结论:布洛芬凝胶剂经离子导入有良好的吸收性.     

Pharmacokinetic considerations in somatic gene therapy

It is anticipated that gene therapies will be useful for achieving long durations of action with little temporal fluctuation in the level of the therapeutic gene product, localized effects in specific tissues or cell types, and levels of biological products that can be regulated over time by drugs or physiological events. The effective clinical application of gene therapies will require detailed consideration of the pharmacokinetics of the gene and its gene product. This requires understanding not only the apparent kinetics of the bioactive gene product, but the intrinsic kinetics of each step involved in gene delivery, gene expression and the bioavailability of the gene product. Numerical models are described for three different approaches to gene therapy: (i) those that involve permanent integration of a transgene into the target cell, (ii) those that involve transient residence of the transgene within the cell, and (iii) those that allow control over gene expression by regulatory factors or administered drugs. Experimental studies describing the dynamics and kinetics of DNA in vivo and early pharmacokinetic studies of viral and non-viral systems are reviewed.     

Pharmacokinetic aspects of rectal formulations of Temazepam

An in vitro/in vivo study was carried out with different rectal formulations of temazepam. Pharmacokinetic data were determined in a cross-over study in 10 volunteers after rectal administration of 10 mg temazepam as a polyethylene glycol based suppository (selected from in vitro data), a liquid-filled capsule and a micro-enema respectively, using oral administration of a liquid-filled capsule as a reference. Serum levels of temazepam indicate an instantaneous and complete release from the micro-enema (F_rel=0.94±0.21, C_max 205±36.9 g/l, t_max 0.49±0.31 hour) and a slower but complete release of temazepam from the suppository (F_rel=1.01±0.25, C_max 202±41.3 g/l, t_max 1.48±0.41 hour). A high interindividual variation in absorption profiles was observed after rectal administration of the liquid-filled capsule (F_rel 0.72±0.36, C_max 182±122 g/l, t_max 4.08±4.28 hour), which makes it less suitable for rectal use. The micro-enema and suppository appear to be useful as rectal formulations for temazepam.     

Therapeutic considerations in using combinations of newer beta-lactam antibiotics

The in vitro activity, pharmacokinetic interactions, and clinical efficacy of newer beta-lactam antibiotic combinations are reviewed. Combinations of beta-lactam antibiotics offer an antimicrobial spectrum similar to that of aminoglycoside-beta-lactam combinations without the renal or eighth cranial nerve toxicity of aminoglycosides. Synergistic activity with beta-lactam combinations is demonstrable in vitro against a wide variety of aerobic gram-negative bacilli, but the frequency, with which it is found is substantially less than for aminoglycoside-beta-lactam combinations. Also, in vitro antagonism can be demonstrated, particularly with combinations containing an agent capable of inducing beta lactamase. Substantial alterations in the pharmacokinetics of cefotaxime and desacetylcefotaxime have been demonstrated by the concomitant administration of mezlocillin or azlocillin. In addition, the clearance of moxalactam has been shown to be reduced by concomitant administration of piperacillin, and the clearance of oxacillin is reduced by concomitant mezlocillin therapy. Dosage reductions of these drugs may be appropriate in certain situations. Several clinical trials comparing therapy with beta-lactam combinations versus aminoglycoside-containing regimens in neutropenic patients have shown no difference in overall efficacy between the two regimens, with the possible exception of infections in persistently granulocytopenic patients and perhaps in patients with Pseudomonas aeruginosa infections. beta-lactam combinations are generally less nephrotoxic, but potentially more costly when newer compounds are included, than amino-glycoside-containing regimens. These beta-lactam combinations should be reserved for use in patients at high risk for aminoglycoside toxicity.     

Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations

Introduction: Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy.

Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (C_max), area under the plasma concentration-time curve (AUC) and elimination half-life (t_½β) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status.

Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.     

3种大黄酚制剂在兔血浆中的药动学研究

目的研究大黄酚脂质体(chrysophanol liposomes)、大黄酚聚氰基丙烯酸丁酯纳米囊(chrysophanol loaded polybu-tylcyanoacrylate,Chry-PBCA-NC)、大黄酚羟丙基-β-环糊精包合物(chrysophanol-hydroxypropyl-β-cyclodextrin inclusion com-plex,Chry-HP-β-CD)在兔血浆内的药动学特征,为优选最佳的大黄酚制剂提供依据。方法将3种制剂各分为高、中、低(9、3、1 mg.kg-1)3个剂量组,分别静脉注射于家兔体内,采用高效液相色谱法测定给药后不同时间点血浆中大黄酚的浓度并计算药动学参数。结果 3种大黄酚制剂的药时曲线下面积随着剂量的增加而增加。在中、高剂量下,大黄酚聚氰基丙烯酸丁酯纳米囊相对于另两种制剂其消除相半衰期差异有显著性。结论 3种大黄酚制剂静注后的血药浓度-时间曲线均符合二室模型,在血浆中消除过程较快,大黄酚聚氰基丙烯酸丁酯纳米囊的消除最为缓慢。     

Pharmacokinetic considerations of perinatal antiretroviral therapy

Antiretroviral therapy (ART) in pregnant women represents a unique combination of therapy and prophylaxis of HIV infection. Until the global epidemic of HIV and the discovery of efficient prevention of perinatal transmission through ART, the world has not witnessed a pharmacologic intervention of such a scale during pregnancy and delivery. The use of ART in pregnancy creates unique challenges in delivering therapeutic agents, targeting the HIV virus in both the pregnant woman and her unborn child, throughout dramatic changes in their physiologic state. With an increased complexity of perinatal ART and the introduction of novel agents into clinical practice, a better understanding of the pharmacokinetics (PK) and pharmacodynamics of ARV drugs is crucial for the safe and most effective use of ARV drugs in women during pregnancy and infants in the first months of life. While PK studies are already difficult to perform during pregnancy, they are particularly challenging in women with HIV infection due to multiple social, economic and cultural constrains. In this paper we provide an overview of published studies of ART disposition during pregnancy, labor, breastfeeding and in the newborn infant after delivery.