CYP3A is the main enzyme subfamily involved in the metabolism of the HIV protease‐inhibitor saquinavir. We hypothesized that individuals homozygous for CYP3A5*1 might have a higher oral clearance of ...saquinavir, compared with subjects lacking functional CYP3A5 alleles. A single‐dose pharmacokinetic trial of saquinavir soft gel capsules, 1,200 mg, was performed in 16 black Tanzanian healthy volunteers with two functional CYP3A5 alleles (*1/*1) and in 18 volunteers without functional CYP3A5 alleles (both alleles being either *3, *6, or *7). The median area under the plasma concentration–time curve (AUC)0–24 reached among subjects with two functional alleles was 1,410 ng h/ml (interquartile range (IQR) 826–1,929), whereas it was 2,138 ng h/ml (IQR 1,380–3,331) in subjects without (P=0.0533, Mann–Whitney U‐test). The median ratio of saquinavir over its M2 plus M3 hydroxy metabolites in urine was 64 (IQR 52–73) in subjects with two functional alleles, whereas it was 145 (IQR 89–181) in those without (P=0.000078, Mann–Whitney U‐test). In conclusion, saquinavir is metabolized by CYP3A5. The median AUC0–24 for saquinavir among individuals with two functional CYP3A5 alleles was 34% lower than among those with no functional alleles. To clarify the clinical importance of the CYP3A5 polymorphism, further studies should be conducted on saquinavir, dosed to steady state, in the presence of ritonavir boosting.
Clinical Pharmacology & Therapeutics (2007) 81, 708–712. doi:10.1038/sj.clpt.6100117; published online 28 February 2007
A reversed-phase high performance liquid chromatographic method was developed and validated for the quantitative determination of amodiaquine (AQ) and its metabolite desethylamodiaquine (DAQ) in ...whole blood collected on filter paper. The structure analogue 4-(4-dimethylamino-1-methylbutylamino)-7-chloroquinoline was used as internal standard. Upon collection, blood was added to 10% phosphoric acid in a 1:1 ratio and then spotted onto filter paper. The samples were alkalinized (pH
≈
9.2) with potassium hydroxide at the time of assay and the compounds were extracted together with internal standard into di-isopropyl ether and then re-extracted into an aqueous phase with 0.1
M phosphate buffer at pH 4. The chromatographic analysis was performed using an Agilent Technologies ChemStation LC System. The absorbance of the compounds was monitored at 333
nm. Mean extraction recoveries of AQ and DAQ were 49 and 48%, respectively. Intra-day and inter-day coefficients of variation were <10.5%. The limit of quantification was 50
nM for both compounds (sample size 100
μl). Both AQ and DAQ that were previously reported to be unstable have been stored on filter paper for at least 19 weeks. The method was applied on samples from healthy volunteers.
A quantitative reverse-phase HPLC method with UV detection, for lumefantrine (LF) and desbutyllumefantrine (DLF) in whole blood spotted on filter paper was developed. The analytes were stabilized on ...filter paper by treatment of blood with phosphoric acid (1.6
mol/L). Halofantrine was used as internal standard and the analytes were extracted from filter paper using methanol. The methanolic extract was extracted with di-isopropylether after addition of acidic phosphate buffer (pH 2). Chromatographic separation was carried out on a Zorbax Eclipse XDB-phenyl column (4.6
mm
×
150
mm, particle size 5
μm) at a flow rate of 1
mL/min using a mobile phase of acetonitrile–ammonium acetate buffer (0.1
M ammonium acetate and 0.01
M acetic acid, pH 6.5) (10:90). The absorbance of the compounds was monitored at 335
nm. The average extraction recovery from filter paper ranged between 45–51% for LF and 25–33% for DLF for a concentration range between 300 and 3000
nM. Inter- and intra-assay coefficients of variation for LF and DLF were ≤9.2. Limits of quantification for LF and DLF were 300
nM. The method has been applied in malaria patients. In conclusion, a simple procedure for blood sampling and quantitative measurement of lumefantrine and desbutyllumefantrine suitable for field studies in resource-limited laboratories was developed.
Background
Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to ...be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV‐infected Ugandans.
Methods
Efavirenz plasma concentrations were obtained for 66 HIV‐infected Ugandans initiating efavirenz‐ based regimens, with blood samples collected at eight time‐points over 24 h on day 1 of treatment, and at a further eight time‐points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz.
Results
The mean steady‐state minimum plasma concentration (Cmin) of efavirenz was 2.9 µg/mL, the mean area under the curve (AUC) was 278.5 h µg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (Cmax) of efavirenz was >4 µg/mL in 96.6% of participants, while Cmin was <1 µg/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2‐week period, and 95% of these participants were found to have efavirenz plasma concentrations >4 µg/mL, although only half maintained a high concentration until at least 8 h after dosing.
Conclusion
The findings of this study show that HIV‐infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to Cmax, regardless of the sampling time.
Quantification of valproic acid in dried blood spots Pohanka, Anton; Mahindi, Margarita; Masquelier, Michèle ...
Scandinavian journal of clinical and laboratory investigation,
10/2014, Letnik:
74, Številka:
7
Journal Article
Recenzirano
Abstract
Background. Therapeutic drug monitoring (TDM) of the antiepileptic drug valproic acid (VPA) is recommended in patients with multiple drug therapy or with concomitant disabilities to ensure ...treatment efficacy and avoid adverse reactions in both adults and children. The use of sampling techniques compatible with home sampling, such as dried blood spot sampling could potentially facilitate this for patients. Aim. To assess the usefulness of a bioanalytical method for quantification of VPA in dried blood spots. Materials and methods. Quantification was based on liquid chromatography-mass spectrometry (LC-MS), both for the DBS method and the plasma-based reference method. Results. The method was validated in the range 10-1200 μmol/L. Total imprecision ranged from 4.9-8.9 (%CV) and accuracy was within ± 14%. Conclusion. The validated method has potential for evaluation in therapeutic drug monitoring in combination with home sampling of DBS. The impact of spot size can be controlled through acceptance criteria and hematocrit in the range 30-60% can be accepted in sampling. Comparison of VPA levels between plasma and whole blood cannot be done without considering the blood-plasma ratio.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A follow-up study was conducted to determine the magnitude of and factors related to adherence to artemether/lumefantrine (ALu) treatment in rural settings in Tanzania. Children in five villages of ...Kilosa District treated at health facilities were followed-up at their homes on Day 7 after the first dose of ALu. For those found to be positive using a rapid diagnostic test for malaria and treated with ALu, their caretakers were interviewed on drug administration habits. In addition, capillary blood samples were collected on Day 7 to determine lumefantrine concentrations. The majority of children (392/444; 88.3%) were reported to have received all doses, in time. Non-adherence was due to untimeliness rather than missing doses and was highest for the last two doses. No significant difference was found between blood lumefantrine concentrations among adherent (median 286
nmol/l) and non-adherent median 261
nmol/l; range 25
nmol/l (limit of quantification) to 9318
nmol/l. Children from less poor households were more likely to adhere to therapy than the poor odds ratio (OR)
=
2.45, 95% CI 1.35–4.45; adjusted OR
=
2.23, 95% CI 1.20–4.13. The high reported rate of adherence to ALu in rural areas is encouraging and needs to be preserved to reduce the risk of emergence of resistant strains. The age-based dosage schedule and lack of adherence to ALu treatment guidelines by health facility staff may explain both the huge variability in observed lumefantrine concentrations and the lack of difference in concentrations between the two groups.
A pre-packaged fixed-dose formulation of chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P) combination (Homapak) is widely used for the treatment of falciparum malaria in Ugandan children. It is ...however a product whose pharmacokinetics and interactions have not been studied.
To explore possible pharmacokinetic interactions between CQ and S/P during co-administration, and to determine their bioavailability in the locally made Homapak compared to the Good Manufacturing Practice (GMP) made formulations.
Thirty-two adult healthy volunteers were randomized into four groups and given single oral doses of fixed-dose CQ+S/P combination (Homapak), or GMP formulations of S/P (Fansidar), CQ (Pharco), or their combination. Plasma samples were followed for 21 days, analysed by HPLC-UV methods, with pharmacokinetic modeling using the WinNonlin software.
Sulfadoxine in Homapak was more rapidly absorbed (ka = 0.55 h(-1)) than in Fansidar + CQ (ka = 0.27 h(-1), p=0.004), but not more than S in Fansidar alone group (ka = 0.32 h(-1), p=0.03). No significant differences were observed in the other pharmacokinetic parameters of S, P and CQ when given together or separately. The relative bioavailability of CQ and S in Homapak showed bioequivalence to reference formulations.
There were no pharmacokinetic interactions between CQ, S and P when the compounds were given together, however, more investigations would be needed to explore this further. Compared with GMP made drugs, both S and CQ are bioequivalent in Homapak, the Ugandan made fixed-dose formulation. Furthermore, the absorption of S was more rapid which could be advantageous in malaria treatment.
Co‐administration of artemether–lumefantrine with milk is recommended to improve lumefantrine (L) absorption but milk may not be available in resource‐limited settings. This study explored the ...effects of cheap local food in Uganda on oral bioavailability of lumefantrine relative to milk. In an open‐label, four‐period crossover study, 13 healthy adult volunteers were randomized to receive a single oral dose of artemether–lumefantrine (80 mg artemether/480 mg lumefantrine) with water, milk, maize porridge or maize porridge with oil on separate occasions. Plasma lumefantrine was assayed using high‐performance liquid chromatography with ultraviolet detection. Pharmacokinetic exposure parameters were determined by non‐compartmental methods using WinNonlin. Peak concentrations (Cmax) and area under concentration–time curve restricted to 48 hr after single dosing (AUC(0–48)) were selected for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. When artemether–lumefantrine was administered with maize porridge plus oil, average bioequivalence ranges (means ratios 90% CI, 0.84–1.88 and 0.85–1.69 for Cmax and AUC(0–48), respectively) were within and exceeded acceptance ranges relative to milk (90% CI, 0.80–1.25). Both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures (bioinequivalence) relative to milk. If milk is not available, it is thus possible to recommend fortification of carbohydrate‐rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine after artemether–lumefantrine administration.
Artemisinin combination therapy (ACT) has been widely adopted as first-line treatment for uncomplicated falciparum malaria. In Uganda, amodiaquine plus artesunate (AQ+AS), is the alternative ...first-line regimen to Coartem(R) (artemether + lumefantrine) for the treatment of uncomplicated falciparum malaria. Currently, there are few field-adapted analytical techniques for monitoring amodiaquine utilization in patients. This study evaluates the field applicability of a new method to determine amodiaquine and its metabolite concentrations in whole blood dried on filter paper.
Twelve patients aged between 1.5 to 8 years with uncomplicated malaria received three standard oral doses of AQ+AS. Filter paper blood samples were collected before drug intake and at six different time points over 28 days period. A new field-adapted sampling procedure and liquid chromatographic method was used for quantitative determination of amodiaquine and its metabolite in whole blood.
The sampling procedure was successively applied in the field. Amodiaquine could be quantified for at least three days and the metabolite up to 28 days. All parasites in all the 12 patients cleared within the first three days of treatment and no adverse drug effects were observed.
The methodology is suitable for field studies. The possibility to determine the concentration of the active metabolite of amodiaquine up to 28 days suggested that the method is sensitive enough to monitor amodiaquine utilization in patients. Amodiaquine plus artesunate seems effective for treatment of falciparum malaria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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