Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection

OBJECTIVE: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection. METHODS: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated. RESULTS: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml. CONCLUSIONS: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.     

Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression

BACKGROUND: In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long-term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single-dose pharmacokinetics and short-term safety of pravastatin in children undergoing regular triple-drug immunosuppressive therapy after cardiac transplantation. METHODS: Nineteen pediatric cardiac transplant recipients (aged 4.4 to 18.9 years) receiving triple immunosuppression therapy consisting of methylprednisolone (19 patients), cyclosporine (INN, cyclosporin) (17 patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 24 hours. Subsequently, the patients took 10 mg pravastatin orally once daily for 8 weeks. The lipid-lowering effect and the safety of pravastatin therapy were studied. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 122.2 +/- 88.2 ng/mL (range, 11.4-305.0 ng/mL), and the area under the plasma concentration-time curve of pravastatin from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL (range, 30.8-701.6 ng.h/mL). These C(max) and AUC(0-10) values are nearly 10-fold higher than the corresponding values reported in hypercholesterolemic children in the absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/- 0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was 1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to those in the hypercholesterolemic children. By 8 weeks of treatment, the concentration of serum total cholesterol decreased by 13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and triglycerides by 6% (not significant, P =.28); the concentration of high-density lipoprotein cholesterol increased by 7% (not significant, P =.30). No clinically significant increases in serum ALT, creatine kinase, or creatinine levels were observed. CONCLUSIONS: The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.     

Pharmacokinetics and pharmacodynamics of daptomycin in a clinical setting

We investigated achievement of a target 24-h area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥666 and the factors influencing this ratio in patients who received daptomycin (DAP) for infectious disease treatment in a clinical setting. The target AUC/MIC was obtained in 6 patients (35.3%) at a 4–6 mg/kg dose (Group_{_4–6 mg/kg}) and in 4 (18.2%) at a >6 mg/kg dose (Group_{_>6 mg/kg}). There was a significant difference in clearance of DAP (CL_{_DAP}) between these groups, but no other difference in characteristics. Multiple linear regression analysis was performed for prediction of AUC ≥666 based on patient factors and the presence or absence of sepsis. In a stepwise analysis, serum creatinine (SCr) was a significant predictor of AUC, but this parameter explained only 13% of the variance in achievement of the target AUC. These results show that the target AUC/MIC may or may not be achieved at the doses used in Group_{_4–6 mg/kg} and Group_{_>6 mg/kg}. Receiver operating characteristic analysis suggested that a CL_{_DAP} >0.450 L/hr may lead to failure to reach the target AUC/MIC. Therefore, regardless of dose, the efficacy of DAP should be monitored closely to prevent failure of infectious disease treatment, particularly because therapeutic drug monitoring of DAP is limited by difficulty measuring the DAP serum concentration at many medical facilities. Our findings are preliminary, and a further study is required to identify factors that increase CL_{_DAP} and to enable dose adjustment of DAP.     

Pharmacokinetics and pharmacodynamics of dilevalol

The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.     

Cardiovascular magnetic resonance findings in a pediatric population with isolated left ventricular non-compaction

Background

Isolated Left Ventricular Non-compaction (LVNC) is an uncommon disorder characterized by the presence of increased trabeculations and deep intertrabecular recesses. In adults, it has been found that Ejection Fraction (EF) decreases significantly as non-compaction severity increases. In children however, there are a few data describing the relation between anatomical characteristics of LVNC and ventricular function. We aimed to find correlations between morphological features and ventricular performance in children and young adolescents with LVNC using Cardiovascular Magnetic Resonance (CMR).

Methods

15 children with LVNC (10 males, mean age 9.7 y.o., range 0.6 - 17 y.o.), underwent a CMR scan. Different morphological measures such as the Compacted Myocardial Mass (CMM), Non-Compaction (NC) to the Compaction (C) distance ratio, Compacted Myocardial Area (CMA) and Non-Compacted Myocardial Area (NCMA), distribution of NC, and the assessment of ventricular wall motion abnormalities were performed to investigate correlations with ventricular performance. EF was considered normal over 53%.

Results

The distribution of non-compaction in children was similar to published adult data with a predilection for apical, mid-inferior and mid-lateral segments. Five patients had systolic dysfunction with decreased EF. The number of affected segments was the strongest predictor of systolic dysfunction, all five patients had greater than 9 affected segments. Basal segments were less commonly affected but they were affected only in these five severe cases.

Conclusion

The segmental pattern of involvement of non-compaction in children is similar to that seen in adults. Systolic dysfunction in children is closely related to the number of affected segments.     

Pharmacokinetics of oral propafenone in patients with supraventricular arrhythmia

The efficacy of propafenone (P), a class IC antiarrhythmic drug with weak beta-blocking properties was studied over a four day period in 10 patients with supraventricular arrhythmias (atrial fibrillation 7, flutter 1 and tachycardia 2). Group 1 included five patients (3M, 2F) who received 300 mg of P on days 1 and 4. Group 2 included five patients (4M, 1F) who received 600 mg on days 1 and 4. All the patients received 1200 mg/day on days 2 and 3. Pharmacokinetics parameters were calculated for the first and the final dosing. Half of the patients were converted to sinus rythm after a delay ranging from 12 to 55 h after the first dosing. The duration of arrhythmia was shorter and the left atrial diameter was significantly lower in the responder group than in the non-responders. No relationship was observed between clinical efficacy and dose or plasma concentration of P. After the first administration of P, major interindividual variability in pharmacokinetic parameters was observed. Seven patients correspond to the extensive metabolizer phenotype with t1/2 el less than 10 h (mean: 5.4 +/- 2.2 SD). In this group t1/2 el increased from day 1 to day 4 and the AUC final/AUC initial ratio ranged between 4 to 17.5. Three patients showed the non-extensive metabolizer phenotype with t1/2 el ranging from 12.4 to 13.7 h and a moderate increase in AUC over chronic dosing. Adverse effects (cardiac conduction abnormalities, visual and digestive disturbances) were observed in the 3 oldest patients (70-73 yrs).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of atenolol in children

The pharmacokinetics and pharmacodynamics of intravenous atenolol were studied in 10 children during cardiac electrophysiologic studies. The intravenous pharmacokinetic data were best described by a two-compartment model and revealed the following (mean +/- SD): total body clearance, 0.15 +/- 0.06 L/hr/kg; volume of the central compartment 0.33 +/- 0.06 L/kg; volume of distribution at steady state, 0.83 +/- 0.15 L/kg; distributive elimination half-life, 0.29 +/- 0.08 hour; and terminal elimination half-life, 4.56 +/- 1.05 hours. The data suggest that children have a slightly shorter terminal elimination half-life than that of adults. Pharmacodynamic data showed a significantly (p less than 0.01) increased sinus cycle length and an increase in His to ventricle conduction time (p less than 0.05). Further studies are necessary to determine the optimal oral dose and dosing frequency of atenolol and to access the response of children to long-term treatment.     

Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis.

OBJECTIVES: We tested the hypotheses that (1) plasma clearance of dichloroacetate is decreased in patients with end-stage cirrhosis, and (2) patients with cirrhosis are vulnerable to dichloroacetate-induced hypoglycemia caused by exaggerated inhibition of hepatic glucose production. METHODS: Seven subjects with cirrhosis and six healthy volunteers received a 5-hour primed constant infusion of 6,6-2H2-glucose. After a 2-hour basal period, subjects received intravenous dichloroacetate, 35 mg/kg, over 30 minutes. Dichloroacetate pharmacokinetics were compared by the mixed-effects population-based technique. Glucose production was calculated by means of isotope dilution. RESULTS: The optimal dichloroacetate pharmacokinetic model for both subjects with cirrhosis and control subjects had two compartments, with all parameters weight normalized. Peak plasma dichloroacetate concentration in subjects with cirrhosis did not differ from that in control subjects, but typical dichloroacetate clearance was only 36% of that in control subjects (P < .001). Dichloroacetate decreased plasma lactate concentration by approximately 50% (P < .001), glucose production by 7% to 9% (P < .05), and plasma glucose concentration by 9% to 14% (P < .05) in both subjects with cirrhosis and control subjects. Dichloroacetate-induced decreases in plasma lactate and glucose concentrations and in glucose production in subjects with cirrhosis did not differ from those in control subjects. CONCLUSIONS: Plasma dichloroacetate clearance is markedly decreased in patients with cirrhosis, likely because of compromised hepatic function. Subjects with cirrhosis exhibit neither exaggerated inhibition of glucose production nor increased risk of hypoglycemia as a result of acute dichloroacetate-induced hypolactatemia.     

Pharmacokinetics and pharmacodynamics of piperaquine in a murine malaria model

Piperaquine (PQ) is an important partner in antimalarial treatment strategies. However, there is a paucity of detailed preclinical and pharmacokinetic data to link PQ serum concentrations and toxicity or efficacy. The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of PQ in a murine malaria treatment model. The study comprised three arms. (i) PQ pharmacokinetic parameters were determined in healthy and malaria-infected mice (90 mg/kg PQ phosphate [PQP]). (ii) For determination of single-dose pharmacodynamics, Swiss mice were inoculated with Plasmodium berghei parasites and given PQP (10, 30, or 90 mg/kg intraperitoneally) at 2 to 5% starting parasitemia. After 60 days, the 90-mg/kg PQP group was reinoculated with P. berghei. (iii) Combination efficacy was investigated at doses of 10 mg/kg PQP and 30 mg/kg dihydroartemisinin (DHA). The median survival times were 4, 10, and 54 days for 0, 10, and 30 mg/kg PQP, respectively. All mice given 90 mg/kg PQP survived beyond 60 days, with a mean parasitemia of <1% before and after reinoculation. The nadir for DHA plus PQP was significantly lower (22-fold +/- 12-fold) than the initial parasitemia for the individual drugs (DHA, 12-fold +/- 5-fold; PQP, 13-fold +/- 3-fold; P = 0.007 [analysis of variance]). The elimination half-lives of PQ in healthy and infected mice were 18 and 16 days, respectively, and the extrapolated residual PQ concentration at 60 days (<10 mug/liter) was ineffective at suppressing P. berghei infection. PQ has a potent antimalarial effect after single-dose treatment, and its efficacy was enhanced by combination with DHA.     

Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.     

Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia

BACKGROUND: Pravastatin is a widely used statin in adults, but its pharmacokinetics in children is not known. Our aim was to determine the single-dose pharmacokinetics and the lipid-lowering effect and safety of short-term administration of pravastatin in children. METHODS: Twenty children (age range, 4.9-15.6 years) with heterozygous familial hypercholesterolemia ingested a single dose of 10 mg pravastatin. Plasma concentrations of pravastatin were measured for up to 10 hours. The patients then took 10 mg pravastatin orally once daily for 8 weeks. The concentration of serum lipids and safety laboratory parameters were measured before and after 8 weeks of treatment. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 15.7 ng/mL (range, 1.6-55.0 ng/mL), and the mean time to reach C(max) was 1.4 hours (range, 0.5-4 hours). The mean elimination half-life of pravastatin was 1.6 hours (range, 0.85-4.2 hours). The area under the plasma concentration-time curve of pravastatin ranged from 5.7 to 58.9 ng. h/mL (mean value, 26.6 ng. h/mL). By 8 weeks of treatment, the serum concentration of total cholesterol had decreased 18% (P <.0001); low-density lipoprotein cholesterol, 21% (P <.0001); and triglycerides, 18% (not significant, P =.18). The concentration of high-density lipoprotein cholesterol had increased 8% (not significant, P =.13). Few transient adverse events occurred. No increases in serum alanine aminotransferase, creatine kinase, or creatinine level were observed. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profile of pravastatin in children is similar to that reported for adults. In the short term, the daily dose of 10 mg pravastatin was well tolerated and moderately effective in decreasing the serum cholesterol concentration. However, further studies are needed on the long-term safety and efficacy of pravastatin in children.     

Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.     

Clinical use of transvenous electrodestruction of the atrioventricular junction in patients with supraventricular tachyarrhythmia

The authors described 51 patients with different types of supraventricular tachyarrhythmias and ciliary arrhythmia paroxysms who showed resistance to drug therapy. All the patients were treated by the closed transvenous electrodestruction of the atrioventricular junction by producing a series of discharges with a defibrillator to the area of His' bundle, the power being 280-400 J. A stable and complete transversal blockade was obtained in 45 patients, in 6 patients the restoration of permeability in the atrioventricular system with frequent ventricular responses was observed, being the reason for repeated electrodestructions. No complications were observed. In the patients with blockade of the I-II degree tachycardia paroxysms either stopped or were milder and subjected to drug therapy. Biologically controlled electrocardiostimulators of the "demand" type were implanted to all patients after electrodestruction of the atrioventricular junction. Proceeding from the above the authors made a conclusion that the closed transvenous electrodestruction was a method of choice in the treatment of supraventricular tachyarrhythmias and ciliary arrhythmia paroxysms who showed resistance to drug therapy. It can be effectively used for seriously ill patients and elderly persons.     

吸入性激素药代学和药效学

吸入性激素（ICS）是一种局部激素，全身性作用极小，已成为哮喘长期治疗的一线药物。本文重点讨论ICS的药效学和药代动力学。     

Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia

The pharmacokinetics, pharmacodynamics, and safety of pravastatin, a new selective 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, were evaluated during monotherapy and with subsequent concomitant cholestyramine therapy in 33 patients with primary hypercholesterolemia in this randomized study. After 4 weeks, pravastatin monotherapy (5 mg, 10 mg, and 20 mg twice daily) significantly decreased total cholesterol by 17% to 24% (p less than 0.001 versus baseline) and low-density lipoprotein cholesterol by 23% to 35% (p less than 0.001). High-density lipoprotein cholesterol increased by 8% to 9%, and triglycerides decreased by 6% to 9%. The area under the serum concentration-time curve and maximum serum concentration of pravastatin showed dose-proportionality; time to maximum serum concentration and serum elimination half-life were independent of dose. When added to pravastatin therapy, cholestyramine enhanced the lipid-lowering effects of pravastatin. After 4 weeks of combination therapy, total cholesterol was reduced by 32% to 38% (p less than 0.001 versus baseline), and low-density lipoprotein cholesterol was reduced by 47% to 56% (p less than 0.001). High-density lipoprotein cholesterol increased by 11% to 18% (p less than 0.05). Pravastatin was well tolerated; no clinical adverse events directly attributable to the drug were reported.     

Complete atrioventricular block and ventricular tachyarrhythmia associated with donepezil

Donepezil is a reversible inhibitor of acetylcholinesterase. Its commonest adverse events are nausea, diarrhoea, malaise, dizziness, and insomnia. Symptomatic cardiac rhythm disturbances associated with the use of donepezil are extremely unusual. An 82 year old patient with Alzheimer's disease (AD) developed complete atrioventricular block and ventricular tachyarrhythmia 1 month after starting treatment with donepezil, and was admitted to the emergency department because of dizziness and syncope. Immediately after admission, a temporary ventricular pacing catheter was placed in the right ventricle. Rhythm was observed to return to a normal sinus rhythm on the fourth day after implantation. Treatment of AD with cholinesterase inhibitors carries a risk of cardiac disturbances. In addition to sinusal bradycardia, it may lead to such major dysrhythmias as complete atrioventricular block and ventricular tachyarrhythmia, as in our case. In this report, we describe symptomatic complete atrioventricular block and ventricular tachyarrhythmia associated with the use of donepezil.