106 research outputs found
Irinotecan: from clinical pharmacokinetics to pharmacogenetics
Four decades ago, a plant alkaloid was isolated from the Chinese tree
Camptotheca acuminata (Nyssaceae family), which showed promising antitumor
activity in vitro (1 ). At that moment, a relatively new class of anticancer agents was
born. Unfortunately, during clinical trials, this alkaloid, called camptothecin (CPT),
showed severe and unpredictable side effects (myelosuppression, diarrhea, and
hemorrhagic cystitis), which were unmanageble during this early chemotherapeutic era
(2-4). Later on, the drug's relative lack of hydrophility was found to be the main reason
for these adverse events.
Despite this ''false starf', renewed interest in this compound was found after the
elucidation of its mechanism of action during the mid-1980s (i.e the inhibition of
topoisomerase I; ref. 5-7). Topoisomerase I is an essential enzyme in DNA replication
and RNA transcription and is present in all eukaryotic cells (8). In the physiologic state
of the cell nucleus, DNA is double-stranded, super-coiled and fits tightly into a
chromosome. To synthesize new DNA, this topological constrained DNA should
unwind. To this end, topoisomerase I binds to the DNA, forms a covalent reversible
adduct (which is called the cleavable complex), cleaves a phosphodiester bond and a
single-strand break occurs (6). Next, the DNA molecule is able to rotate freely around
its intact single strand, and relaxation of DNA takes place. After the religation of the
cleavage, the enzyme dissociates from DNA. The cleavable complex usually binds for
a short period, just to allow the single strand to unwind (9, 1 0). CPT induces the
stabilization of the cleavable complexes (11, 12), what will lead to a disruption of the
DNA-strand when the replication fork meets the cleavable complex (7). This doublestrand
break will lead to the activation of apoptosis pathways and ultimately result in
cell-death (7).
In subsequent years, various derivatives of CPT with improved water solubility
have been developed, of which irinotecan (CPT-11) was considered to be among the
most promising ones (13). It is a semisynthetic water-soluble prodrug, with minor
intrinsic cy1otoxic activity. After administration, the drug is partially converted into the
1 00- to 1 ,000-times more active metabolite SN-38 by the enzyme carboxyl esterase
(14-17). In the liver, SN-38 is de-toxified by undine-diphosphate
glucuronosyltransferase 1 A isoforms, whereby SN-38-glucuronide is formed (18). All
these compounds can be secreted into the bile by specific transporters (19). In the
intestines, several bacteria produce ~-glucuronidase, which enables re-activatation of
the glucuronidated form of SN-38 (20). Relatively high concentrations of SN-38 will
lead to damage of the bowel mucosa, which results in one of the drug's most
prominent side effects: diarrhea (21). In addition, irinotecan can also be oxidated by
cy1ochrome P450 isozymes (22, 23), which will lead to the formation of several inactive
metabolites, including APC and NPC
Recent Clinical Developments of Nanomediated Drug Delivery Systems of Taxanes for the Treatment of Cancer
Conventional taxanes are used as cornerstone of the chemotherapeutical treatment
for a variety of malignancies. Nevertheless, a large proportion of patients do not benefit from
their treatment while they do suffer from severe adverse events related to the solvent or to the
active compound. Cremophor EL and polysorbate 80 free formulations, conjugates, oral
formulations and different types of drug delivery systems are some examples of the several
attempts to improve the treatment with taxanes. In this review article, we discuss recent
clinical developments of nanomediated drug delivery systems of taxanes for the treatment of
cancer. Targeting mechanisms of drug delivery systems and characteristics of the most
commonly used taxane-containing drug delivery systems in the clinical setting will be
discussed in this review
Pharmacological and clinical aspects of immediate release fentanyl preparations: Criteria for selection
In palliative care, pain management is often hampered by episodes of breakthrough pain, characterised by a rapid onset and, on average, duration less than 1 h. Until recently, only immediate release morphine and oxycodon preparations were available for the treatment of these episodes but time until effect is too long for both of these drugs. Recently, immediate release fentanyl products have become available for the treatment of breakthrough pain. These products can be classified as oromucosal and nasal products. Both are absorbed rapidly by the mucosa, although the oromucosally delivered products are partly absorbed by the gastrointestinal tract and therefore reach maximum plasma levels somewhat slower (after 30-90 min) than the nasally delivered products (after ~15 min). In clinical placebo controlled studies, all new immediate release fentanyl products were proven to be effective from 15 min after administration in the treatment of breakthrough pain. The first studies comparing immediate release fentanyl with immediate release morphine or oxycodon also found superiority for the new fentanyl products
Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics
Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters coul
Quantification of afatinib, alectinib, crizotinib and osimertinib in human plasma by liquid chromatography/triple-quadrupole mass spectrometry; focusing on the stability of osimertinib
The development and full validation of a sensitive and selective ultra-performance liquid chromatography/
tandem mass spectrometry (UPLC–MS/MS) method are described for the simultaneous analysis of afatinib,
alectinib, crizotinib and osimertinib in human lithium heparinized plasma. Afatinib-d6, crizotinib-d5 and erlotinib-d6 were used as internal standards. Given osimertinib's instability in plasma and whole blood at ambient
temperature, samples should be solely processed on ice (T = 0 °C). Chromatographic separation was obtained on
an Acquity UPLC ® BEH C18; 2.1 × 50 mm, 1.7 μm column, which was eluted with 0.400 mL/minute flow on a
linear gradient, consisting of 10 mM ammonium formate (pH 4.5) and acetonitrile. Calibration curves for all
compounds were linear for concentration ranges of 1.00 to 100 ng/mL for afatinib and 10.0 to 1000 ng/mL for
alectinib, crizotinib and osimertinib, herewith validating the lower limits of quantification at 1.00 ng/mL for
afatinib and 10.0 ng/mL for alectinib, crizotinib and osimertinib. Within-run and between-run precision measurements fell within 10.2%, with accuracy ranging from 89.2 to 110%
Inhibition of OATP1B1 by tyrosine kinase inhibitors: In vitro-in vivo correlations
Background:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.Methods:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.Results:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.Conclusion: These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters
Effects of St. John's wort on irinotecan metabolism
St. John's wort (SJW), a widely used herbal product, has been implicated
in drug interactions resulting from the induced expression of the
cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of
SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known
substrate for CYP3A4. Five cancer patients were treated with irinotecan
(350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg
daily, orally for 18 days) in an unblinded, randomized crossover study
design. The plasma levels of the active metabolite SN-38 decreased by 42%
(95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with
1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7
micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033,
two-sided paired Student's t test). Consequently, the degree of
myelosuppression was substantially worse in the absence of SJW. These
findings indicate that patients on irinotecan treatment should refrain
from taking SJW because plasma levels of SN-38 were dramatically reduced,
which may have a deleterious impact on treatment outcome
Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents
Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patients dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA1.7 m2, 1.7 m2 BSA1.9 m 2, BSA1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m 2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between 14% and 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P=0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure
A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours
Background: CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies,
CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation
study is the first-in-human study with CPC634.
Methods: adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W)
(part 1, dose range 15–100 mg/m2
), 2-weekly (Q2W) (part 2, 45 mg/m2
) or Q3W with dexamethasone premedication (part 3, 60 mg/m2
).
Results: thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and
at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional\ud
pharmacokinetic profile. At 60 mg/m2
, the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the
peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel.
Conclusion: CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin
toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication
Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice
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