Karin Fattinger
University of Bern
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Clinical Pharmacology & Therapeutics | 1991
Karin Fattinger; Samuel Vozeh; Arni Olafsson; Jiri Vlcek; Markus Wenk; Ferenc Follath
Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two‐compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug‐level monitoring in a well‐defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.
European Journal of Pharmaceutical Sciences | 2010
Jacek Hajda; Katharina Rentsch; Christoph Gubler; Hans C. Steinert; Bruno Stieger; Karin Fattinger
Garlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95% CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95% CI, 67-112%), relative to baseline in both cases. For the erythromycin breath test performed, the average result was 96% (95% CI, 83-112%). Ingestion of garlic extract had no effect on drug and metabolite AUCs following a single dose of simvastatin or pravastatin, although the average area under the plasma concentration curve (AUC) of saquinavir decreased to 85% (95% CI, 66-109%), and changes in intestinal P-glycoprotein expression negatively correlated with this change. In conclusion, garlic extract induces intestinal expression of P-glycoprotein independent of cytochrome P450 3A4 in human intestine and liver.
Journal of Pharmacokinetics and Biopharmaceutics | 1995
Karin Fattinger; Davide Verotta
In a pharmacokinetics context deconvolution facilitates the following: (i) Given data obtained after intravascular (generally intravenous) input one may estimate the disposition function; (ii) given the disposition function and data obtained after extravascular administration one may estimate the extravascular to vascular input rate function. In general if the data can be represented by the convolution of two functions, of which one is unknown, deconvolution allows the estimation of the unknown one. Attention has been given in the past to deconvolution and in particular to its nonparametric variants. However, in a population context (multiple observations collected in each of a group of subjects) the use of nonparametric deconvolution is limited to either analyzing each subject separately or to analyzing the aggregate response from the population without specifying subject-specific characteristics. To our knowledge a fully nonparametric deconvolution method in which subject specificity is explicitly taken into account has not been reported. To do so we use so-called “longitudinal splines”. A longitudinal spline is a nonparametric function composed of a template spline, in common to all subjects, and of a distortion spline representing the difference of the subjects function from the template. Using longitudinal splines for input rate or disposition function one obtains a solution to the problem of taking subject specificity into account in a nonparametric deconvolution context. To obtain estimates of longitudinal splines we consider three different methods: (1) parametric nonlinear mixed effect, (2) least squares, and (3) two-stage. Results obtained in one simulated and two real data analyses are shown.
Biometrics | 1995
Karin Fattinger; Lewis B. Sheiner; Davide Verotta
This article presents a new approach for exploring the distribution of interindividual random effects in nonlinear mixed effect models. The approach introduces a spline function, which transforms an assumed normally distributed interindividual random effect to an arbitrary distribution approximating that of the data. The performance of this tool is illustrated using simulated pharmacokinetic data with non-normally distributed random effects. Results of the analyses of two real kinetic data sets are also presented.
British Journal of Clinical Pharmacology | 2008
Ulrike Halbsguth; Katharina Rentsch; Dominique Eich-Höchli; Isabel Diterich; Karin Fattinger
AIMSnIn the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose.nnnMETHODSnOpioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose.nnnRESULTSnThe maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol).nnnCONCLUSIONSnOral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.
European Journal of Clinical Pharmacology | 2000
Karin Fattinger; Neal L. Benowitz; R. T. Jones; Davide Verotta
AbstractObjective: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa.nn Methods: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution.nn Results: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45u2009min after ingestion. The median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10u2009min and 45u2009min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19% (95% CI: 11–26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23–37%) of total systemic cocaine exposure.nn Conclusions: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability.
Journal of Pharmacokinetics and Biopharmaceutics | 1995
Karin Fattinger; Davide Verotta
A lot of attention has been given in the past to deconvolution and in particular to its nonparametric variants: In a companion paper (1), we present a fully nonparametric deconvolution method in which subject specificity is explicity taken into account. To do so we use so-called “longitudinal splines.” A longitudinal spline is a nonparametric function composed of a template spline, in common to all subjects, and of a distortion spline representing the difference of the subjects function from the template. In this paper we concentrate on testing and documenting the performance of this nonparametric methodology in terms of the approximation of unknown functions. We simulate population data using parametric functions, and use longitudinal splines to recover the unknown functions. We consider different estimation methods including (1) parametric nonlinear mixed effect, (2) least squares, and (3) two-stage. Methods 2–3 are more robust than Method 1, and obtain reliable estimates of the unknown functions. The lack of robustness of Method 1 appears to be due to the misspecifications of the distribution of the subjects parameters. Results also suggest that in a data-rich situation nonparametric nonlinear mixed-effect models should be preferred.
European Journal of Pharmaceutical Sciences | 2009
Ludwig Perger; Katharina Rentsch; Gerd A. Kullak-Ublick; Davide Verotta; Karin Fattinger
In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (+/-S.D.) immediate and extended release doses were 719+/-297 and 956+/-404 mg, with high absolute morphine bioavailabilities of 56-61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10-15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only approximately 30% of maximal immediate release absorption being reached after 10 min and maintained for 3-4h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.
Journal of Nutrition | 2015
Andreas Schild; Isabelle Herter-Aeberli; Karin Fattinger; Sarah Anderegg; Tim Schulze-König; Christof Vockenhuber; Hans-Arno Synal; Heike A. Bischoff-Ferrari; Peter Weber; Arnold von Eckardstein; Michael B. Zimmermann
BACKGROUNDnEnsuring adequate vitamin D status in older adults may reduce the risk of osteoporosis. The serum 25-hydroxyvitamin D [25(OH)D] concentration is the recommended biomarker of vitamin D status, but the optimal serum 25(OH)D concentration for bone health in postmenopausal women remains unclear.nnnOBJECTIVEnThe aim of this study was to apply the highly sensitive (41)Ca skeletal labeling technique and the measurement of urinary (41)Ca:(40)Ca ratios to determine the serum 25(OH)D concentration that has greatest benefit on bone calcium flux in postmenopausal women.nnnMETHODSnWe administered a mean intravenous (41)Ca dose of 870 pmol to healthy postmenopausal women [n = 24, age (mean ± SD): 64 ± 6.0 y] without osteoporosis. After 6 mo, at the nadir of their wintertime serum 25(OH)D status, each of the women sequentially consumed daily oral cholecalciferol supplements of 10, 25, and 50 μg/d (in this order), each for 3 mo. We assessed serum 25(OH)D concentrations monthly and urinary (41)Ca:(40)Ca ratios biweekly. (41)Ca:(40)Ca ratios were measured with low-energy accelerator mass spectrometry. With the use of pharmacokinetic analysis, we determined the effect of varying serum 25(OH)D concentrations on (41)Ca transfer rates.nnnRESULTSnAt baseline, the mean (95% CI) serum 25(OH)D concentration was 16.2 (13.5, 18.8) μg/L. After the first, second, and third intervention periods, mean (95% CI) serum 25(OH)D increased to 29.8 (27.2, 32.4), 36.9 (34.2, 39.7), and 46.6 (41.2, 52.0) μg/L, respectively. Supplementation was associated with a downward shift in the urinary (41)Ca:(40)Ca ratio compared with the predicted (41)Ca:(40)Ca ratio without vitamin D supplementation. In the model, the most likely site of action of the increase in serum 25(OH)D was transfer from the central compartment to a fast exchanging compartment. At this transfer rate, predicted values were a concentration with half-maximal effect of 2.33 μg/L and an estimate of the maximal effect of 31.7%. After the first, second, and third intervention periods, the mean changes in this transfer rate were +18.0%, +25.7%, and +28.5%, respectively.nnnCONCLUSIONnIn healthy postmenopausal women, increasing serum 25(OH)D primarily affects calcium transfer from the central compartment to a fast exchanging compartment; it is possible that this represents transfer from the extracellular space to the surface of bone. A serum 25(OH)D concentration of ~40 μg/L achieves ~90% of the expected maximal effect on this transfer rate. This trial was registered at clinicaltrials.gov as NCT01053481.
European Journal of Clinical Pharmacology | 2009
Ulrike Halbsguth; Stefanie Schwanda; Thomas Lehmann; Sonja Ostheeren-Michaelis; Karin Fattinger
Vasculitis is a heterogeneous group of diseases characterised by inflammation of blood vessel walls. It can affect vessels of varying size and location, resulting in fibrosis, thrombus formation and necrosis. While some patients show clinical and laboratory signs of vasculitis, others have few or unspecific symptoms. Among other causative factors, adverse drug reactions are a common cause of vasculitis. Drug-related vasculitis usually affects small arterioles and venules, predominantly in the skin, but sometimes also in the internal organs [1]. Approximately 20% of all cases of dermal vasculitis are related to adverse drug reactions [2]. A broad range of substances have been associated with vasculitis, including catecholamines (e.g. ephedrine, phenylpropanolamine), drugs of abuse (amphetamine, cocaine) and antibiotics, such as penicillins and sulfonamides [3–5]. This case report describes a 52-year-old woman referred to the University Hospital Zurich with a rash suggestive of cutaneous vasculitis. She reported having taken a “Mexican herbal medicine” for weight reduction that she had obtained from her hairdresser. The herbal medicine was labelled as containing several herbs and hydrochlorothiazide. After 4 weeks of taking this supplement twice daily, the patient suffered from flu-like symptoms of varying intensity for 1 week during which time she took one ibuprofen pill. The symptoms resolved spontaneously, but 1 month later she experienced itching on her trunk, hands and feet. Dark-red, painful, palpable skin lesions several centimetres in diameter and central necrosis appeared symmetrically on both legs (Fig. 1a). The supplement regimen was discontinued. Physical examination, laboratory results, electrocardiogram, chest radiographs and cerebral magnetic resonance imaging revealed no abnormalities, particularly no traces of further vascular lesions. Viral or bacterial infections, rheumatic or coagulation disorders and malignant disease were considered during diagnosis, but were not supported by subsequent tests. The skin biopsy showed leucocytoclastic vasculitis and fibrinoid necrosis of the vessels, fibrin thrombi of the capillaries and venules and immunocomplex deposits [fibrinogen, C3 and immunoglobulin (Ig)M] in the vessel walls (Fig. 1b). The haemorrhagic necrotising vasculitis Eur J Clin Pharmacol (2009) 65:647–648 DOI 10.1007/s00228-009-0632-9