Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
Background: The purpose of our study was to develop a physiologically based pharmacokinetic (PBPK) model describing the behavior of lidocaine in humans by scaling up physiological variables from ...animal models of cardiac arrest. We attempted to identify the optimal dose regime for lidocaine during cardiac arrest using this model.
Methods and results: We designed a flow-dependent PBPK model representing nine body tissues for lidocaine. Physiological organ flow rates, tissue volumes, and plasma-tissue partition parameters for lidocaine in humans were taken from the literature. Data from published animal studies were used to estimate loss of organ blood flow during cardiac arrest and lidocaine tissue partition coefficients. The model assumed a 70 kg cardiac arrest patient. The following five lidocaine dose regimes were simulated: (1) 4 mg/kg IV push (IVP) (2) 1.5 mg/kg IVP then 1.5 mg/kg IVP in 4 min, (3) 3 mg/kg IVP, (4) 2 mg/kg IVP, and (5) 1.5 mg/kg IVP. A simulation of Regimen 2, which is the current American Heart Association (AHA) recommendation, suggests that the concentration of lidocaine is suboptimal at the decision point (3–5 min) to administer another dose. Regimen 4 offers a slightly more rapid progress towards optimal cardiac concentrations and more acceptable brain concentrations compared to regimes 1–3.
Conclusion: Simulations from our PBPK model suggest that the current AHA lidocaine dose regime for cardiac arrest may not result in optimal lidocaine concentrations in the heart and brain. Simulations suggest that 2 mg/kg IVP may be the most acceptable lidocaine dose regime during cardiac arrest.
Introdução: O objectivo deste estudo foi desenvolver um modelo farmacocinético baseado na fisiologia (PBPK) descrevendo o comportamento da lidocaı́na em humanos a partir de um modelo animal de paragem cardio respiratória (PCR) Procuramos identificar, com este modelo, o melhor regime de administração de lidocaı́na durante a paragem cardı́aca.
Método e Resultados: Desenhamos um modelo PBPK para a lidocaı́na, dependente do fluxo, representando 9 tecidos corporais. Os parâmetros de perfusão fisiológica dos órgãos, volumes tecidulares, e coeficientes de partição plasma-tecido para a lidocaı́na em humanos foram retirados da literatura. Foram também utilizados resultados de estudos animais para determinar a perda de volume sanguı́neo durante a PCR e os coeficientes de partição tecidular da lidocaı́na. O modelo assumiu um doente de 70 Kg em PCR. Foram simulados as seguintes doses de lidocaı́na: (1) 4 mg/Kg iv directa; (2) 1.5 mg/Kg iv directa seguido da mesma dose em 4 minutos; (3) 3 mg/Kg iv directa; (4) 2 mg/Kg iv directa; (5) 1.5 mg/Kg iv directa. A simulação do regime 2, que corresponde á recomendação actual da American Heart Association (AHA), sugere que a concentração de lidocaı́na é sub-óptima aos 3-5 minutos que é o ponto de decisão para nova administração. As concentrações cardı́acas óptimas são atingidas ligeiramente mais depressa no regime 4 e as concentrações cerebrais também são mais aceitáveis do que nos regimes 1-3.
Conclusão: As simulações realizadas com o nosso modelo PBPK sugere que a lidocaı́na na PCR administrada segundo a recomendação da AHA não atinge concentrações óptimas no coração e no cérebro. Esta simulação sugere ainda que a utilização de 2 mg/Kg pode ser a dose mais adequada durante a PCR.
The safety and efficiency of a novel method of rapid-infusion IV immunoglobulin (IVIg) were retrospectively reviewed in 50 patients with neuromuscular disorders. There were 89 adverse events after ...341 rapid infusions (26%), 3.5% of which were considered to be major (requiring hospitalization) and 66% minor. All patients recovered without sequelae, and there were no deaths. Fourteen of 17 patients (82%) receiving maintenance therapy preferred rapid IVIg infusion because of its convenience. Rapid-infusion IVIg can be given safely and conveniently in many patients with neuromuscular disorders.
OBJECTIVE:
To examine the relationship between preadmission indicators of 49 PharmD students entering their first professional year at a new school of pharmacy and their scores on a Basic Math Skills ...Test (BMST). A secondary objective was to determine what factors, if any, contributed to the successful completion of the BMST.
METHODS:
This cross-sectional investigation used a convenience sample of PharmD students entering the first professional year at a three-year-old, private, southeastern school of pharmacy. All first-year students who took the mandatory BMST, as part of a math mentor pilot program, were eligible for enrollment. The BMST covered nine different competencies and was validated at the grade-8 level. Math test scores, the student's Pharmacy College Admissions Test (PCAT), and other demographic and scholastic information was obtained from the student's application file in a retrospective manner. All identifiers were removed before the data were submitted to the investigators.
RESULTS:
Statistical analysis suggested that two preadmission indicators strongly influenced BMST performance: percentile scores on the quantitative section of the PCAT (PCAT—QP) and whether the student attended a private or public university prior to admission to the pharmacy school. In addition, four factors significantly contributed to successful completion of the BMST: math/science grade point average (MS-GPA), PCAT percentile scores, PCAT—QP percentile scores, and the number of BMST items left blank.
CONCLUSIONS:
A relationship exists between preadmission indicators of PharmD students entering their first professional year and their BMST score. In addition, certain identifiable factors impact BMST scores of first-year PharmD students. Admissions committees may find this useful in identifying students who may need remedial math assistance prior to beginning math-intensive courses such as pharmaceutical calculations and pharmacokinetics.
To determine the chemical compatibility of three different triple drug admixtures diluted with either 5% dextrose in water or 0.9% NaCl solution when administered via a multiple line infusion system ...(Omni-Flow 4000, Abbott Laboratories, Abbott Park, IL). The triple drug admixtures were: a) dobutamine, dopamine, and norepinephrine; b) nitroglycerin, sodium nitroprusside, and dobutamine; and c) nitroglycerin, dopamine, and dobutamine.
Two phase in vitro compatibility study.
Pharmaceutical laboratory.
None.
Phase I assessed chemical stability when the triple drug admixture was placed in a single container. In phase II, individual drug components of the admixtures were infused via the multiple line infusion system. Samples were collected at time 0, 1 hr, 2 hrs, 4 hrs, 12 hrs, and 24 hrs. All samples were frozen and stored at -70 degrees C until assayed.
Samples were assayed using stability-indicating high performance liquid chromatography. The triple drug admixtures were considered to be chemically stable if there was < or = 10% loss of stated potency over 24 hrs. In phase I, chemical stability was observed for all triple drug admixtures at 24 hrs. In phase II, dobutamine, dopamine, norepinephrine, and sodium nitroprusside showed chemical stability at 24 hrs. Nitroglycerin showed a two-fold increase in concentration at 24 hrs compared with the initial concentration through the test infusion system; however, this amount was still one third lower than originally anticipated.
All triple drug admixtures were chemically stable when placed in single containers. Dobutamine, norepinephrine, and sodium nitroprusside showed chemical stability when delivered via a multiple line infusion system. The reduced recovery of nitroglycerin from the test infusion system may result from adsorption of the nitroglycerin to the polyvinyl chloride plastic cassette and tubing during infusion.
The objective of this study was to review current changes in the pharmacologic management of cardiac arrest (ventricular fibrillation, pulseless ventricular tachycardia, asystole, and ...electromechanical dissociation) as put fourth by the American Heart Association's 1992 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care. We concluded that the 1992 Guidelines provide a reference base for all clinicians involved in emergency cardiac care. The newly revised recommendations are classified on the basis of the true clinical merit of the intervention, for example, an intervention that has been proved effective (i.e., high-dose epinephrine) versus one that is possibly effective (i.e., high-dose epinephrine). The preferred intravenous fluid to be used in resuscitation is saline solution or lactated ringers solution because of possible adverse neurologic outcomes seen with dextrose-containing fluids. The dose of all drugs administered via the endotracheal route should be 2 to 2.5 times the intravenous dose. Modifications in the dose or dosing interval have been recommended for epinephrine, atropine, lidocaine, bretylium, and procainamide during cardiopulmonary resuscitation. Options for high-dose epinephrine therapy are offered, but neither recommended or discouraged. Magnesium sulfate has been added for the management of torsades de points, severe hypomagnesemia, or refractory ventricular fibrillation. The maximum total dose of atropine in the treatment of asystole and electromechanical dissociation has been increased from 2 mg to 0.04 mg/kg. The use of sodium bicarbonate should be limited to the treatment of hyperkalemia, tricyclic antidepressant overdose, overdoses requiring urinary alkalinization, or preexisting bicarbonate sensitive acidosis.
Over-the-counter histamine2-blocker therapy Gonzalez, E R; Grillo, J A
Annals of pharmacotherapy/The annals of pharmacotherapy,
03/1994, Volume:
28, Issue:
3
Journal Article
Peer reviewed
Open access
In determining whether a prescription medication should be granted OTC status, the risks and benefits of treatment with the medication must be weighed. Ultimately, the decision must be made with some ...degree of uncertainty. Pharmacists must take advantage of this uncertainty to demonstrate their professional expertise and value to society. The Rx-to-OTC switch for H2-blockers may benefit many, although not all, patients with acid peptic complaints, and it offers pharmacists an opportunity to demonstrate their willingness and ability to assist in the use of cost-effective OTC drug therapy.
Congenital syphilis continues to be a substantial public health problem in many parts of the world. Since the first use of penicillin for the treatment of syphilis in 1943, which was a notable early ...success, it has remained the preferred and standard treatment including for congenital syphilis. However, the treatment of congenital syphilis is largely based on clinical experience and there is extremely limited evidence on the optimal dose or duration of administration of penicillin or the use of other antibiotics.
To assess the effectiveness and safety of antibiotic treatment for newborns with confirmed, highly probable and possible congenital syphilis.
We searched the Cochrane STI Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, WHO ICTRP, ClinicalTrials.gov and Web of Science to 23 May 2018. We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies.
Randomised controlled trials (RCTs) comparing antibiotic treatment (any concentration, frequency, duration and route) with no intervention or any other antibiotic treatment for neonates with confirmed, highly probable or possible congenital syphilis.
All review authors independently assessed trials for inclusion, extracted data and assessed the risk of bias in the included studies. We resolved any disagreements through consensus. We assessed the quality of the evidence using the GRADE approach.
Two RCTs (191 participants) met our inclusion criteria and none of these trials was funded by the industry. One trial (22 participants) compared benzathine penicillin with no intervention for infants with possible congenital syphilis. Low-quality evidence suggested that benzathine penicillin administration may not have decreased the rate of neonatal death due to any cause (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.06 to 11.70), and showed a possible reduction into the proportion of neonates with clinical manifestations of congenital syphilis (RR 0.12, 95% CI 0.01 to 2.09). Penicillin administration increased the serological cure at the third month (RR 2.13, 95% CI 1.06 to 4.27). These results should be taken with caution, because the trial was stopped early because there were four cases with clinical congenital syphilis in the no treatment group and none in the treatment group. Interim analysis suggested this difference was significant. This study did not report neonatal death due to congenital syphilis or the frequency of serious or minor adverse events after therapy. We downgraded the quality of evidence because of imprecision and risk of bias.One trial (169 participants) compared benzathine penicillin versus procaine benzylpenicillin. High- and moderate-quality evidence suggested that there were probably no differences between benzathine penicillin and procaine benzylpenicillin for the outcomes: absence of clinical manifestations of congenital syphilis (RR 1.00, 95% CI 0.97 to 1.03) and serological cure (RR 1.00, 95% CI 0.97 to 1.03). There were no cases of neonatal death due congenital syphilis; all 152 babies who followed up survived. This study did not report on the frequency of serious or minor adverse events after therapy. We downgraded the quality of evidence because of serious risk of bias.
At present, the evidence on the effectiveness and safety of antibiotic treatment for newborns with confirmed, highly probable or possible congenital syphilis is sparse, implying that we are uncertain about the estimated effect. One trial compared benzathine penicillin with no intervention for infants with possible congenital syphilis. Low-quality evidence suggested penicillin administration possibly reduce the proportion of neonates with clinical manifestations of congenital syphilis, penicillin administration increased the serological cure at the third month. These findings support the clinical use of penicillin in neonates with confirmed, highly probable or possible congenital syphilis. High- and moderate-quality evidence suggests that there are probably no differences between benzathine penicillin and procaine benzylpenicillin administration for the outcomes of absence of clinical manifestations of syphilis or serological cure.
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