Pharmacokinetic-pharmacodynamic modelling of oxprenolol in man using continuous non-invasive blood pressure monitoring

Summary The relationship between the plasma concentration of oxprenolol and its haemodynamic effects during physical exercise was studied in 6 healthy volunteers, in whom BP and heart rate (HR) were continuously monitored by non-invasive techniques (Fin-A-Press-Tonometer) during repeated three-minute exercise periods for 8 h after treatment. Using the fitted pharmacokinetic curve, the drug effect was related to its plasma concentration using the E_max model.The mean EC50 for the relationship between drug concentration and heart rate during exercise (HR_ex) was 73.1 ng/ml, and for systolic blood pressure during exercise (SBP_ex) it was 112.7 ng/ml. E_max was 29.0% for HR_ex, and 33.2% for SBP_ex. There were no consistent differences between the parameters for the effects on HR_ex and SPB_ex.Thus, using a new, non-invasive technique for continuous measurement of blood pressure, the effect of a beta-adrenoceptor blocking drug on SBP_ex was described with similar accuracy as its effect on HR_ex.     

Pharmacokinetic-pharmacodynamic (PK-PD) modelling in non-steady-state studies and arterio-venous drug concentration differences.

In conducting a non-steady-state pharmacokinetic (PK)-pharmacodynamic (PD) study there is potential for the observed effect (E) vs time, and venous plasma drug concentration (C) vs time, profiles to display temporal displacement with respect to each other. This is most frequently observed when there exists a distributional nonequilibrium across the effect organ giving rise to hysteresis, i.e. observed C preceding E in the time domain, with the resulting potential for a counterclockwise loop to be generated in the observed E vs C plot (when data are connected in time-order). Such temporal displacement does not afford direct prediction of the steady-state E vs C PD relationship. When an arterio-venous (A-V) difference exists across the tissues of the blood sampling compartment (i.e. the arm), and this arises solely from an elimination process then drug concentration in the respective peripheral arterial plasma and venous plasma compartments will be in equilibrium at all times during a non-steady-state PK experiment. If there are no other sources of temporal displacement in the relationship between E and C then the observed E vs C plot will be a direct predictor of the steady-state E vs C PD relationship. In contrast when the A-V difference is of a distributional nature then proteresis, i.e. observed E preceding C in the time domain, will arise with the potential for the generation of a clockwise loop in the observed E vs C relationship. Simulated error-incorporated E vs time, and C vs time, data was analysed by semi-parametric implementation of an effect-compartment link-model that affords accurate steady-state E vs C PD predictions (without the requirement of sampling arterial blood) from data that incorporates the concurrent presence of: (i) distributional nonequilibrium across the effect organ, and (ii) distributional A-V non-equilibrium. Accurate steady-state E vs C PD predictions were achieved irrespective of the comparative magnitudes of the two nonequilibria, i.e. whether the rate of equilibration across the effect organ was faster than, or slower than, the rate of equilibration across the arm (resulting in a clockwise or counterclockwise loop in the observed E vs C plot, respectively), or indeed if one or other of the nonequilibria is essentially absent. When the rate of equilibration across the effect organ is slower than the rate of A-V equilibration (i.e. counterclockwise loop generated in the observed E vs C plot) then the need to model for the underlying A-V nonequilibrium is redundant, i.e. accurate steady-state E vs C PD predictions can be achieved with implementation (strictly incorrectly) of a more simple link parameterised solely to model for distributional nonequilibrium across the effect organ.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of magnesium sulfate on the calcium-stimulated adenosine triphosphatase activity and lipid peroxidation of red blood cell membranes from preeclamptic women

The effect of the treatment with magnesium sulfate (MgSO(4)) on Ca-ATPase activity and level of lipid peroxidation of red blood cells from preeclamptic pregnant women was examined because it is known that these parameters are affected with preeclampsia. Red cell ghosts from 11 normotensive and 11 preeclamptic pregnant women, before and after treatment with MgSO(4), were assayed for Ca-ATPase activity and level of lipid peroxidation, determined as TBARS or conjugated dienes. It was found that the Ca-ATPase activity is significantly lower and the level of lipid peroxidation is significantly higher in the preeclamptic women with no treatment, as compared to normotensive pregnant women. Both parameters return to normal values after the MgSO(4) therapy. These results can be mimicked by in vitro preincubation with MgSO(4) of intact red blood cells from preeclamptic pregnant women, without any treatment. Our data indicate that MgSO(4) treatment of preeclamptic pregnant women modifies both the Ca-ATPase activity and the level of lipid peroxidation of their red blood cell membranes, reaching values similar to those of normotensive pregnant women. The diminution of the level of lipid peroxidation by MgSO(4), can account for the increase in Ca-ATPase activity.     

Effect of an angiotensin II analogue upon blood pressure, plasma renin concentration and plasma aldosterone in hypertensive patients

Succinamyl-arg-val-tyr-val-his-pro-phenylglycine acetate (succinamyl1-val5-phenylglycine acetate3-A II), an analogue of angiotensin II, has a pressor effect upon patients suffering from primary and secondary hypertension regardless of prevailing plasma renin concentration. It stimulates the release of aldosterone, whereas plasma renin concentration is not influenced. It is concluded, that this new analogue is, as far as its effect upon blood pressure and release of aldosterone in man is concerned, an agonist of angiotensin II.     

Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

AIMS: To develop a pharmacokinetic-pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations. METHODS: Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic-pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP). RESULTS: The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [alpha = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg(-1), between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg. CONCLUSION: Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.     

Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. a minireview

Abstract: Pain is characterized by its multi‐dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state‐of‐the‐art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so‐called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time‐course of plasma concentrations of morphine did not always reflect the time‐course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R‐O‐demethyl‐tramadol metabolite. For ‘stronger’ opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ‐opioid receptors. Different models have been proposed to describe the time‐course of buprenorphine. An effect‐compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine‐6‐glucuronide (M6G). A longer blood‐effect site equilibration half‐life t_1/2k_e0 was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t_1/2k_e0 for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time‐course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.     

Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold,blood pressure,and salivary flow

Summary Although clonidine analgesia appears to be mediated by the same central ₂-adrenoceptors that mediate its hypotensive effect, it is short-lasting when compared to the fall in blood pressure. This has been investigated by combined pharmacokinetic-pharmacodynamic analysis in 10 healthy volunteers who received (double-blind and crossover) clonidine 200 g orally + placebo i.v. and clonidine orally + naloxone i.v. (2.8 mg/5 h). Analgesia was assessed by measuring the subjective (VAS) and objective (R_III) pain thresholds after transcutaneous electrical stimulations of the sural nerve; the mean arterial blood pressure (MAP), salivary flow (SF), and plasma clonidine concentrations were also monitored. A combined pharmacokinetic (first order absorption — 1 compartment) — pharmacodynamic (linear) model, including a hypothetical effect compartment with and without tolerance, were fitted to the data.Clonidine and clonidine + naloxone increased subjective and objective pain thresholds for 4 h. The concentration-effect plot for MAP showed distinct hysteresis. The t_1/2s for effect compartment equilibration were 29 and 42 min for clonidine + naloxone and clonidine. The concentration-effect curves for R_III had the same shape as MAP but the starting hysteresis suddenly collapsed, suggesting acute tolerance. The best fit was obtained with a model where the linear relationship between concentration in the effect compartment and analgesia changed acutely after the third hour.The short-lived analgesia was probably related to an acute change in pain sensitivity induced by food, suggesting that it is not mediated solely by the ₂-adrenoceptors responsible for hypotension.Presented in part at the XIth International Congress of Pharmacology, Amsterdam, July 1990     

Effects of once daily indapamide and pindolol on blood pressure,plasma aldosterone concentration and plasma renin activity in a general practice setting

Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide (2.5 mg daily) and pindolol (10 mg daily) on blood pressure, heart rate, plasma renin activity and plasma aldosterone concentration. There were four randomised test phases of eight weeks each during which patients received indapamide alone, pindolol alone, indapamide plus pindolol and no active treatment (placebo). Blood pressure and heart rate were measured every two weeks. Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase, 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase. Factorial analysis confirmed that the hypotensive effects of the two drugs were additive, without evidence of potentiation or antagonism. Indapamide caused significant reductions in plasma potassium and chloride, and increases in plasma bicarbonate and urate concentrations; it also caused increases in plasma renin activity and aldosterone concentration. These changes are similar to those observed with thiazide diuretics.     

Pharmacokinetic-pharmacodynamic modelling of antibacterial activity of cefpodoxime and cefixime in in vitro kinetic models

The bacterial time-kill curves of cefpodoxime and cefixime against four bacterial strains (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae/penicillin sensitive and S. pneumoniae/penicillin intermediate) were compared in in vitro infection models in which various human pharmacokinetic profiles of unbound antibiotic were simulated. This approach offers more detailed information than the minimum inhibitory concentration (MIC) does about the time course of antibacterial efficacy of an antibiotic. A pharmacokinetic-pharmacodynamic (PK-PD) model based on unbound antibiotic concentrations at the site of infection, and a sigmoid Emax-relationship with EC50 as the antibiotic concentration necessary to produce 50% of the maximum effect, effectively described the antimicrobial efficacy of both cefpodoxime and cefixime. The EC50 values of cefpodoxime and cefixime were consistent with their respective MIC values. Both antibiotics had similar high potency against H. influenzae (EC50: 0.04 mg/L) and M. catarrhalis (EC50: 0.12 mg/L), while the potency of cefpodoxime against S. pneumoniae strains was about 10-fold higher than that of cefixime (EC50s/sensitive strain: 0.02 mg/L versus 0.27 mg/L; EC50s/intermediate strain: 0.09 mg/L versus 0.69 mg/L). Applications of this model and unbound tissue PK profiles obtained from a previous clinical study performed in our group, showed that cefpodoxime has higher bacteriological potency than cefixime against S. pneumoniae. Simulations based on this model allow the comparison of antibacterial efficacy of different antibiotics and dosing regimens.     

Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats.

1. The purpose of this investigation was to examine in vivo drug-concentration anticonvulsant effect relationships of oxazepam in individual rats following administration of a single dose. 2. Whole blood concentration vs time profiles of oxazepam were determined following administration of doses of 4, 8 and 12 mg kg-1. The pharmacokinetics could be described by an open 2-compartment pharmacokinetic model. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of clearance and volume of distribution were 28 +/- 2 ml min-1 kg-1 and 2.6 +/- 0.31 kg-1, respectively, and were not significantly different from the values obtained at the other doses. 3. The anticonvulsant effect was quantitated by a new technique which allows repetitive determination of the convulsive threshold by direct cortical stimulation within one rat. Significant dose-dependent elevations of the seizure threshold were observed. 4. By pharmacokinetic-pharmacodynamic modelling, a log-linear relationship was found between concentration and anticonvulsant effect. Following 12 mg kg-1 the values (mean +/- s.e., n = 11) of the pharmacodynamic parameters slope and minimal effective concentration (Cmin) were 243 +/- 27 microA and 0.11 +/- 0.02 mg l-1, respectively and not significantly different from the values obtained at the other doses. 5. In a repeatability study the pharmacodynamic parameters were determined twice on two different occasions with an interval of two weeks in the same group of 11 rats. The inter-animal variability in the pharmacodynamic parameter slope was 46%, whereas the intra-animal variability was 24 +/- 18%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic-pharmacodynamic modelling of fluvoxamine 5-HT transporter occupancy in rat frontal cortex

BACKGROUND AND PURPOSE: The pharmacokinetic-pharmacodynamic (PK-PD) correlation of fluvoxamine 5-HT transporter (SERT) occupancy was determined in rat frontal cortex ex vivo. EXPERIMENTAL APPROACH: Rats (n=47) with permanent arterial and venous cannulas received a 30 min intravenous infusion of fluvoxamine (1 or 7.3 mg kg(-1)). At various time points after dosing, brains were collected for determination of fluvoxamine concentration and SERT occupancy. In addition, the time course of fluvoxamine concentration in plasma was determined up to the time of brain collection. In a separate study (n=26), the time course of fluvoxamine concentration in brain extracellular fluid (ECF) and plasma was determined. The results of the investigations were interpreted by nonlinear mixed effects modeling. KEY RESULTS: Highest SERT occupancy was reached at the first time point (10 or 15 min) and maintained for 1.5 and 7 h after 1 and 7.3 mg kg(-1), respectively. Thereafter, SERT occupancy decreased linearly at a rate of 8% h(-1). SERT occupancy could be directly related to plasma, brain ECF and brain tissue concentrations by a hyperbolic function (Bmax model). Maximal SERT occupancy (Bmax) was 95%. Estimated concentrations at half-maximal SERT occupancy (EC50) in plasma, ECF and brain tissue were 0.48, 0.22 and 14.8 ng mL(-1) respectively. The minimum value of the objective function decreased 12 points for ECF and brain tissue concentrations relative to plasma (P<0.01), presumably as a result of nonlinear brain distribution. CONCLUSIONS AND IMPLICATIONS: The proposed PK-PD model constitutes a useful basis for prediction of the time course of ex vivo SERT occupancy in behavioural studies with selective serotonin reuptake inhibitors.