NEW MICROBIOLOGICA, 30, 346-349, 2007 Pharmacokinetics and pharmacodynamics in HAART and antibiotic therapy Marta Boffito St. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK
Therapeutic agents used to inhibit the HIV replication are used in combination. The achievement of effective plas-ma concentrations of the drug in its active form, and sustaining such concentrations for the duration of a dosinginterval without exceeding thresholds of toxicity is fundamental in HIV therapy. The issues determining the absorp-tion, biotransformation, distribution to and activity at the intended site, and elimination, are myriad and complex. Studies at molecular, cell, and tissue levels are useful for predicting the possible fate of these agents in vivo, butthe wide inter individual variability shown in whole-body pharmacokinetic studies is illustrative of the difficultyin making general statements rather than more guarded recommendations. KEY WORDS: Antiretroviral drugs, Drug interactions, Pharmacology, HIV infection
inhibitors (NRTIs) are the current backbone ofvirtually all HAART combinations. NRTIs are pro-
The long-term success of highly active anti-
drugs because the active moiety is the triphos-
retroviral therapy (HAART) depends on main-
phate anabolite that is formed intracellularly.
taining concentrations of active drug at the site
NRTI-triphosphates elicit their anti-HIV effect via
of HIV replication sufficient to suppress viral repli-
the inhibition of HIV reverse transcriptase, and
cation and prevent the development of resistance.
presumably toxicity via the inhibition of mito-
Although plasma concentrations of non-nucleo-
chondrial DNA polymerase gamma. Therefore,
side reverse transcriptase inhibitors (NNRTIs) and
the use of these compounds depends upon a
protease inhibitors (PI) have been correlated with
quantitative understanding of the clinical phar-
virological outcome, there are persistent questions
macology of intracellular NRTI-triphosphates
on the use of drug plasma concentration moni-
toring to guide treatment. Theoretically, the high-
Further, therapeutic drug monitoring is available
er the trough concentration (measured at the end
only for NNRTIs and PIs. Before this test can be
of the dosing interval), the better the inhibition
widely applied to routine antiretroviral therapy
of HIV (Boffito et al., 2005).
management, large scale clinical trials should ide-
However, precise therapeutic concentration
ally be completed to demonstrate its utility.
ranges have not been identified for all anti-
However, this presents a considerable challenge
retroviral drugs. Nucleoside reverse transcriptase
and at the moment there are a series of clinicalscenarios, such as hepatic impairment, in chil-
dren, in women or in particular ethnic groups and
during pregnancy, where therapeutic drug mon-
itoring may be considered (Gazzard et al., 2006).
Importantly, drug concentrations alone are not
Chelsea and Westminster HospitalLondon, UK
the ultimate determinant of treatment outcome;
other important factors include tolerability,
Pharmacokinetics and pharmacodynamics in HAART and antibiotic therapy
safety, adherence, treatment history, and resist-
tatin activity (which includes the sum of ator-
vastatin and two of its active metabolites)increased by 79%. By contrast, pravastatinexposure declined by 50%. These data are of
utmost clinical importance since all statins havethe capacity for severe toxicity, including rhab-
Clinically relevant antiretroviral drug-drug inter-
actions may occur among antiretroviral drugsbelonging to the same or to different classes or
Drug-drug interactions involving efavirenz
between antiretroviral drugs and drugs received
Metabolism induction by efavirenz may decrease
by HIV positive patients for the treatment of co-
PI exposure and therefore higher PI and/or riton-
existing medical conditions, the treatment and pre-
vention of opportunistic infections, for support-
In fact, the recommended dose of lopinavir/riton-
ive care or for the limitation of adverse events
avir with efavirenz was 533/133 mg twice daily
caused by antiretroviral agents (Boffito et al., 2005).
(addition of one capsule). Data on the dose of
It is worth noting that despite the well known
the new lopinavir/ritonavir formulation (tablet)
mechanisms behind drug interactions involving
that must be administered in the presence of
NNRTIs and PIs (i.e. metabolism by cytochrome
efavirenz are unclear and further studies are
P450, CYP450, isoenzymes in the gastrointesti-
needed (Kaletra 2006). The dosage regimen of
nal tract and liver), other potential mechanisms
boosted twice daily fosamprenavir/ritonavir
involving such interactions are emerging (i.e.
(700/100 mg) does not require modification with
transporters, gastric pH-dependent absorption).
efavirenz while the addition of 100 mg twice daily
Examples of important drug-drug interactions
of ritonavir is recommended if fosamprenavir is
used once daily (Lexiva 2006). The effect of efavirenz on the pharmacokinetics
of pravastatin, atorvastatin and simvastatin in
Metabolic disturbances associated with HIV
HIV negative volunteers has also been studied
infection and HAART are common. How best to
and appeared to be safe (Fichtenbaum et al.,
treat these events is a pharmacological challenge
2002). From a pharmacokinetic perspective,
because of the potential for clinically relevant
efavirenz is a potent inducer of simvastatin
drug-drug interactions associated with lipid low-
metabolism (leading to a 60% decrease in its plas-
ma concentrations) and a less potent, but still
inhibitors, also known as statins, and antiretro-
significant, inducer of atorvastatin metabolism
viral agents (Fichtenbaum et al., 2002).
(35% decrease in exposure). Non-steady-state
The primary route of metabolism for most statins
exposure of efavirenz did not change, this needs
is via oxidation utilizing the CYP450 3A4 path-
to be confirmed by steady-state data. Higher
way. Pravastatin, fluvastatin and rosuvastatin are
doses should be considered for simvastatin when
exceptions since they follow different metabol-
ic/elimination pathways. The lactone drugs, like
It has been reported that efavirenz and nevirap-
lovastatin and simvastatin, which are adminis-
tered as pro-drugs, are avid substrates for
methadone (Neuman et al., 2006) and that tai-
CYP3A4 and as such are inhibited by CYP3A4
loring the appropriate methadone coverage in
inhibitors, which include the PIs and especial-
efavirenz recipients can be problematic for the
ly ritonavir (Fichtenbaum et al., 2002).
first few weeks of therapy. This has been recent-
Drug interaction studies have been performed
ly confirmed in presence of the NRTI abacavir
with PIs and statins (Fichtenbaum et al., 2002).
(also responsible for an accelerated methadone
Co-administration of saquinavir/ritonavir to
clearance), where the marked reduction in
HIV negative volunteers resulted in increased
methadone concentrations was compensated by
exposure to the active form of simvastatin by
a methadone dose increase of approximately 30%,
up to 60 weeks following antiretroviral initiation
increased by 343%, although the total atorvas-
Protease inhibitors and gastric acid reducing
ciation with 40 mg of omeprazole. Addition of
100 mg of atazanavir or eight ounces of cola
Chemical factors can affect drug absorption by
influencing the state of the drug in the gas-
omeprazole on atazanavir absorption.
trointestinal tract. The absorption of PIs is like-
Co-administration of high dose ranitidine (300
ly to be decreased in the absence of gastric acid-
ity. Therefore, interactions between PIs and anti-
decrease amprenavir AUC by 30% while the Cmin
acid drugs are theoretically possible.
was unchanged, suggesting a lack of effect of the
This is important since a prevalence of 49.8% of
higher gastric pH on trough concentrations.
nausea/anorexia/upper gastrointestinal symptoms
These data, however, was not confirmed by a mul-
has been reported by a large national cohort
tiple dose study investigating the interaction
study (Mathews et al., 2000), and confirmed by
between esomeprazole, a potent proton pump
a recent report investigating gastrointestinal acid-
inhibitor, and fosamprenavir (with and without
ity in HIV-infected subjects (Luber et al., 2004).
ritonavir), where amprenavir plasma exposure
This suggests the frequent use of drugs able to
was unchanged in the presence of esomeprazole
control these symptoms, including anti-acidic
drugs (H antagonists, acid neutralizers and phos-
More studies are needed to confirm which PIs
phate binders, proton pump inhibitors).
can be administered in presence of an altered gas-
Available data suggest that there may be profound
tric pH and how this may impact plasma con-
differences across PIs in terms of absorption
centrations and therefore virological response.
dependence on gastric pH and, therefore, in
It has been argued that ritonavir boosting may
terms of the influence that anti-acidic drugs may
not be capable of counterbalancing the effect of
anti acidic drugs on PI availability. Therefore, this
Atazanavir and indinavir have been shown to
option should be thoroughly investigated as well.
exhibit significantly decreased absorption whengiven with anti-acid drugs. The area under thecurve (AUC) and minimum concentration (C
of atazanavir (400 mg once daily) was reducedby 84 and 87% when administered with buffered
The pharmacology of the different classes of anti-
didanosine (a didanosine formulation with
retroviral agents is quite complex. Despite the
cation chelating agents similar to Maalox) while
expanded knowledge on the role of the hepatic
the AUC of fosamprenavir (1400 twice daily) was
CYP450 isoenzyme system in drug interactions,
reduced by only 18%, with no significant effect
drug interactions are often unpredictable.
Several different mechanisms can be responsi-
Maalox. The deleterious effect of buffered drugs
ble for interactions involving antiretrovirals, and
on atazanavir absorption may be counterbal-
these are complex and generally unclear.
anced by administering atazanavir two hours
Consequently, therapeutic drug monitoring
before or one hour after administration of these
could be considered in this setting to confirm that
drugs, while for H receptor antagonists (rani-
adequate (not too low or too high and therefore
tidine) the two drugs should be administered as
subtherapeutic or toxic) plasma concentrations
far apart as possible, e.g. 12 hours. Conversely,
are being achieved. There are numerous data-
given the prolonged effect of the proton pump
bases that list all specific drug interactions that
inhibitors and major decrease in atazanavir con-
have been observed in HIV clinical practice and
centrations with these drugs, this interaction can-
that scientists believe may be likely.
not be managed by separating atazanavir and theproton pump inhibitor doses. In fact, a recent warning issued by the manu-
facturing company revealed that steady-stateatazanavir C
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Pharmaceutical Law & Industry Report® Reproduced with permission from Pharmaceutical Law & Industry Report, 11 PLIR , 9/20/13. Copyright 2013 byThe Bureau of National Affairs, Inc. (800-372-1033) http://www.bna.comInterpreting Actavis , Young said that even though thegeneric defendants in the Nexium case did not receivePlaintiffs’ Antitrust Claims May Proceedany kind of dir
METHOD ® ’: AN APPLIED PSYCHOLOGICAL ABSTRACT: This study presents the results of an online questionnaire for a novel smoking cessation treatment utilising applied psychological techniques. Participants were 107 paying clients attending Rob Kelly’s Cambridge Clinic. Post treatment 92.5% of participants reported that they had stopped smoking. INTRODUCTION: Cigarette smoking has a high ri