The HEXACO Personality Space Before and After Re-Rotation to Approximate the Big Five Dimensions.

We re-oriented the HEXACO personality dimensions to approximate the Big Five, using two measures of the Big Five as targets in a derivation sample and then in cross-validation samples. The HEXACO approximations of Big Five Agreeableness represented blends of HEXACO Agreeableness, Emotionality, and Honesty-Humility. The HEXACO approximations of Big Five Neuroticism represented blends of Emotionality with low Agreeableness and low Extraversion. The residual sixth dimension, unrelated to the Big Five, contrasted Honesty-Humility with HEXACO Agreeableness. We then examined, in additional samples, some correlates of the original and re-rotated HEXACO dimensions. In the original HEXACO factor space, Honesty-Humility was the strongest correlate of unethical behaviors (selfishness and cheating), participant age, and "assumed similarity" to a friend or partner. Upon re-rotation of the HEXACO factors, associations involving these variables were divided between Big Five Agreeableness and the residual sixth dimension. Sex differences were mainly associated with Emotionality but after re-rotation of the HEXACO factors were divided between Big Five Agreeableness and Neuroticism. We discuss the relative merits of the original and Big Five-targeted HEXACO dimensions with reference to the practical utility of Big Five Agreeableness and Neuroticism and the simplicity and theoretical interpretability of the original HEXACO factors.

Psychological and physiological effects of extended DMT.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

N, N-dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an in vitro investigation.

N, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high-resolution mass spectrometry for metabolite identification.DMT was rapidly metabolised by CYP2D6, while stable with all other investigated CYP enzymes. The metabolism of DMT in HLM was reduced after inclusion of harmine and SKF-525A whereas quinidine did not affect the metabolic rate, likely due to MAO-A residues present in HLM. Analysis of the CYP2D6 incubates showed formation of mono-, di- and tri-oxygenated metabolites, likely as a result of hydroxylation on the indole core.More research is needed to investigate the role of this metabolic pathway in vivo and any pharmacological activity of the proposed metabolites. Our findings may impact on safety issues following intake of ayahuasca in slow CYP2D6 metabolizers or with concomitant use of CYP2D6 inhibitors.

Optimized infusion rates for N,N-dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework.

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half-life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic intensity using population pharmacokinetic/pharmacodynamic modeling. As a secondary aim, the impact of choosing a continuous variable or a bounded integer pharmacokinetic/pharmacodynamic model to inform such an infusion protocol was investigated. A previously published continuous variable model and two newly developed bounded integer models were used to assess optimal doses for achieving a target response. Simulations were performed to identify an optimal combination of a bolus dose and an infusion rate. Based on the simulations, optimal doses to achieve intensity ratings between 7 and 9 (possible range = 0-10) were a bolus dose of 16 mg DMT fumarate followed by an infusion rate of 1.4 mg/min based on the continuous variable model and 14 mg with 1.2 mg/min for the two bounded integer models. However, the proportion within target was low (<53%) for all models, indicating that individual dose adjustments would be necessary. Furthermore, some differences between the models were observed. The bounded integer models generally predicted lower proportions within a target of 7-9 with higher proportions exceeding target compared with the continuous variable model. However, results varied depending on target response with the major differences observed at the boundaries of the scale.

N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokinetic/pharmacodynamic analysis.

N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokinetic/pharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel-Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel-Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC50,e ) were estimated at 71, 137, and 54 nM for alpha, beta, and Lempel-Ziv complexity, respectively. A large amount of between-subject variability was associated with both beta power and Lempel-Ziv complexity with coefficients of variability of 75% and 77% for the corresponding EC50,e values, respectively. Alpha power appeared to be the most robust response, with a between-subject variability in EC50,e of 29%. Having a deeper understanding of these processes might prove beneficial in choosing appropriate doses and response biomarkers in the future clinical development of DMT.

Population pharmacokinetic/pharmacodynamic modeling of the psychedelic experience induced by N,N-dimethyltryptamine - Implications for dose considerations.

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data were obtained from 13 healthy subjects after intravenous administration of DMT. The data were analyzed using nonlinear mixed-effects modeling in NONMEM. DMT plasma concentrations were described by a two-compartment model with first-order elimination leading to formation of the major metabolite indole 3-acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid maximum effect (Emax ) response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with the concentration of DMT at the effect site required to produce half of the maximum response estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was zero, 2, 4, 8, and 9 after doses of 1, 4, 7, 14, and 20 mg, respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.

Effects of Enzyme Induction and Polymorphism on the Pharmacokinetics of Isoniazid and Rifampin in Tuberculosis/HIV Patients.

Tuberculosis is the most common cause of death in HIV-infected individuals. Rifampin and isoniazid are the backbones of the current first-line antitubercular therapy. The aim of the present study was to describe the time-dependent pharmacokinetics and pharmacogenetics of rifampin and isoniazid and to quantitatively evaluate the drug-drug interaction between rifampin and isoniazid in patients coinfected with HIV. Plasma concentrations of isoniazid, acetyl-isoniazid, isonicotinic acid, rifampin, and 25-desacetylrifampin from 40 HIV therapy-naive patients were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after the first dose and at steady state of antitubercular therapy. Patients were genotyped for determination of acetylator status and CYP2C19 phenotype. Nonlinear mixed-effects models were developed to describe the pharmacokinetic data. The model estimated an autoinduction of both rifampin bioavailability (0.5-fold) and clearance (2.3-fold). 25-Desacetylrifampin clearance was 2.1-fold higher at steady state than after the first dose. Additionally, ultrarapid CYP2C19 metabolizers had a 2-fold-higher rifampin clearance at steady state than intermediate or extensive metabolizers. An induction of isonicotinic acid formation from isoniazid dependent on total rifampin dose was estimated. Simulations indicated a 30% lower isoniazid exposure at steady state during administration of standard rifampin doses than isoniazid exposure in noninduced individuals. Rifampin exposure was correlated with CYP2C19 polymorphism, and rifampin administration may increase exposure to toxic metabolites by isoniazid in patients. Both findings may influence the risk of treatment failure, resistance development, and toxicity and require further investigation, especially with regard to ongoing high-dose rifampin trials.

Oral Metronidazole Desensitization for Immunoglobulin E (IgE)-Mediated Hypersensitivity.

Low efficacy has been reported for the treatment of Trichomonas vaginalis with antimicrobial agents other than the 5-nitroimidazole class. Patients with immunoglobulin E (IgE)-mediated hypersensitivity reactions to drugs in this class, including metronidazole and tinidazole, may benefit from a desensitization treatment. We present two patients with past medical histories of IgE-mediated hypersensitivity reactions to metronidazole who were successfully treated with metronidazole using a modified protocol. The first patient was a 39-year-old female diagnosed with trichomoniasis who had a previous reaction to metronidazole characterized by urticaria and pruritus. The second patient was a 53-year-old female who had a history of untreated trichomoniasis due to a previous anaphylactic reaction to metronidazole. Both patients were successfully treated in the intensive care unit (ICU) without signs and symptoms of the reaction. Physicians may use a desensitization protocol for patients with a presumed IgE-mediated hypersensitivity when only the 5-nitroimidazole class is efficacious for the treatment of trichomoniasis.

Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy.

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.

Development and application of a highly sensitive LC-MS/MS method for simultaneous quantification of N,N-dimethyltryptamine and two of its metabolites in human plasma.

A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated. Chromatography was performed using a diphenyl column with gradient elution (0.1% formic acid in methanol/water). The mass spectrometer was operated in multiple reaction monitoring mode. A methanolic solution containing internal standards 2-methylindole 3-acetic acid and deuterated DMT, was added to plasma samples, followed by protein precipitation with acetonitrile. The samples were centrifuged and supernatants transferred to new tubes and evaporated to dryness before reconstitution in aqueous mobile phase. The method was validated with regards to accuracy, precision, sensitivity, selectivity, recovery, matrix effects, stability, carry-over and dilution integrity. The validated linear range was 0.25-200 nM for DMT and 15-250 nM for DMT N-oxide. For the endogenous compound indole-3-acetic acid a different approach was taken due to its significant presence in blank samples. The change in signal response from a blank sample was used when constructing the calibration curve with linearity demonstrated between elevations of 500-5000 nM above the blank. Applicability of the described method was demonstrated through analysis of plasma samples from healthy volunteers having received intravenous injections of DMT. The presented method for rapid and sensitive quantification of DMT and its metabolites in human plasma can be applied to future studies aiming to characterize DMT disposition and its relationship to immediate psychedelic or long-term antidepressive effects.

On the relations between HEXACO agreeableness (versus anger) and honesty-humility.

The HEXACO personality factors of Agreeableness-versus-Anger (A) and Honesty-Humility (H) are interpreted as two complementary aspects of reciprocal altruistic tendency. Here we consider several ways of representing the positive associations between the defining traits of A and of H, through common factor analysis of self-report HEXACO Personality Inventory-Revised (HEXACO-PI-R) facet scale scores (N ≈ 111,000). We describe orthogonal solutions that differ in the extent to which H facets show secondary loadings on A (and vice versa), as well as an oblique solution compatible with a higher-order "cooperativeness" factor. We discuss the psychological plausibility of these solutions, and we review research showing differential associations of several phenomena or outcomes with A and H. We conclude that the optimal representation of A/H trait associations is not yet known but that the value of separate A and H factor scales is well established.

Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV.

OBJECTIVES: To evaluate the effects of concomitant efavirenz-based ART and genetic polymorphism on the variability in rifampicin and 25-desacetylrifampicin pharmacokinetics. PATIENTS AND METHODS: Plasma concentrations of rifampicin and 25-desacetylrifampicin from 63 patients coinfected with TB and HIV were analysed by LC-MS/MS followed by non-linear mixed-effects modelling. Patients were genotyped for SLCO1B1 (463 C>A, 388 A>G, 11187 G>A, rs4149015, 521 T>C and 1436 G>C) and SLCO1B3 (334 T>G). RESULTS: One-compartment disposition models described the observations adequately. The oral clearances of rifampicin and 25-desacetylrifampicin were 140% and 110% higher, respectively, in patients on concomitant efavirenz-based ART. Rifampicin bioavailability was also lower in patients on concomitant ART. Further, although not included in the final model, a lower relative bioavailability in carriers of WT SLCO1B3 334 T>G compared with carriers of mutations in the genotype was estimated. CONCLUSIONS: The results presented indicate both pre-systemic and systemic induction by efavirenz-based ART affecting rifampicin pharmacokinetics. The described drug-drug interaction has a clinical impact on rifampicin exposure prior to steady state and may impact the early bactericidal activity in patients on efavirenz-based ART.

Enantiospecific antitrypanosomal in vitro activity of eflornithine.

The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 µM (95% confidence interval [8.1; 10]), 5.5 µM [4.5; 6.6], and 50 µM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.

Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing.

Pyrazinamide is a first-line drug used in the treatment of tuberculosis. High exposure to pyrazinamide and its metabolites may result in hepatotoxicity, whereas low exposure to pyrazinamide has been correlated with treatment failure of first-line antitubercular therapy. The aim of this study was to describe the pharmacokinetics and metabolism of pyrazinamide in patients coinfected with tuberculosis and HIV. We further aimed to identify demographic and clinical factors which affect the pharmacokinetics of pyrazinamide and its metabolites in order to suggest individualized dosing regimens. Plasma concentrations of pyrazinamide, pyrazinoic acid, and 5-hydroxypyrazinamide from 63 Rwandan patients coinfected with tuberculosis and HIV were determined by liquid chromatography-tandem mass spectrometry followed by nonlinear mixed-effects modeling. Females had a close to 50% higher relative pyrazinamide bioavailability compared to males. The distribution volumes of pyrazinamide and both metabolites were lower in patients on concomitant efavirenz-based HIV therapy. Furthermore, there was a linear relationship between serum creatinine and oral clearance of pyrazinoic acid. Simulations indicated that increasing doses from 25 mg/kg of body weight to 35 mg/kg and 50 mg/kg in females and males, respectively, would result in adequate exposure with regard to suggested thresholds and increase probability of target attainment to >0.9 for a MIC of 25 mg/liter. Further, lowering the dose by 40% in patients with high serum creatinine would prevent accumulation of toxic metabolites. Individualized dosing is proposed to decrease variability in exposure to pyrazinamide and its metabolites. Reducing the variability in exposure may lower the risk of treatment failure and resistance development.

A review of personality/religiousness associations.

We review research on personality/religiousness associations, integrating earlier meta-analyses with recent large-sample online studies. We find that general religiousness shows small positive associations with broad personality factors (e.g. HEXACO Honesty-Humility, Big Five Agreeableness, Conscientiousness) and somewhat stronger positive associations with narrower personality traits involving prosocial tendencies (e.g. altruism, fairness, forgivingness). The link between religiousness and prosociality appears not to be an artifact of self-report method variance. Religious fundamentalism and spirituality show negative and positive associations, respectively, with the Openness factor of personality. Religiousness/personality associations tend to be weak in relatively non-religious countries but moderately strong in highly religious countries. The direction of causal influence between personality and religiousness is not yet clear. Religiousness shows modest negative associations with IQ and appears to be somewhat negatively related to scientific thinking.

Chiral Chromatographic Isolation on Milligram Scale of the Human African Trypanosomiasis Treatment d- and l-Eflornithine.

Eflornithine is a recommended treatment against the otherwise fatal parasitic disease late stage human African trypanosomiasis (HAT), also known as Gambian sleeping sickness. It is administered repeatedly as a racemic mixture intravenously (IV) together with oral nifurtimox. Racemic eflornithine has been investigated in clinical trials for oral dosing. However, due to low systemic exposures at a maximum tolerated oral dose, the drug is continued to be administered IV. The eflornithine enantiomers, d- and l-eflornithine, have different affinities to the target enzyme ornithine decarboxylase, suggesting that the pharmacodynamics of the enantiomers may differ. The aim of this study was to develop a method for isolation of d- and l-eflornithine from a racemic mixture. Several chiral stationary phases (CSPs) were evaluated for enantioselectivity using supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). None of the tested CSPs rendered separation of the enantiomers in SFC mode. Separation of the enantiomers with SFC on the CSP Chiralpak IG was only achieved on an analytical scale after derivatization with ortho-phthalaldehyde (OPA). This was the first reported enantioselective SFC method for an eflornithine derivate. However, due to poor stability, the eflornithine-OPA derivates degraded and no chemically pure enantiomers were obtained. The CSP that showed enantioselectivity in HPLC mode was Chirobiotic R, which resulted in a successful isolation on a semipreparative milligram scale. The isolated eflornithine enantiomers will be tested in nonclinical in vitro and in vivo studies to support and assess the feasibility of a future clinical program with an oral HAT treatment.

Ab initio Description of Bond Breaking in Large Electric Fields.

Strong (10^{10} V/m) electric fields capable of inducing atomic bond breaking represent a powerful tool for surface chemistry. However, their exact effects are difficult to predict due to a lack of suitable tools to probe their associated atomic-scale mechanisms. Here we introduce a generalized dipole correction for charged repeated-slab models that controls the electric field on both sides of the slab, thereby enabling direct theoretical treatment of field-induced bond-breaking events. As a prototype application, we consider field evaporation from a kinked W surface. We reveal two qualitatively different desorption mechanisms that can be selected by the magnitude of the applied field.

Sex differences in HEXACO personality characteristics across countries and ethnicities.

OBJECTIVE: We examined sex differences in the HEXACO Personality Inventory-Revised (HEXACO-PI-R) factor- and facet-level scales and the associations of national sex differences in those scales with national characteristics such as wealth and gender equality. METHOD: HEXACO-PI-R self-reports were collected online from persons in 48 countries (N = 347,192). RESULTS: (1) Women averaged substantially higher than men in Emotionality and in Honesty-Humility, with (sample-unweighted) mean differences across countries of d = 0.84 and d = 0.37, respectively; (2) the HEXACO-PI-R factor scales showed a rather large multivariate sex difference (D > 1 in most countries), about 19% larger than found in similar samples with the Big Five personality factors, (3) some facet scales belonging to the same factor showed widely varying sex differences, (4) national-level sex differences in Emotionality were larger in wealthy and gender-egalitarian countries, replicating previous counterintuitive findings, but such a tendency was not clearly observed for Honesty-Humility, and (5) within several English-speaking countries, sex differences in Emotionality showed comparatively little ethnic variation, suggesting that societal characteristics may influence the size of sex differences in Emotionality. CONCLUSION: The HEXACO model of personality structure provides some new insights in understanding sex differences in personality at the individual and national levels.

Model-Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co-Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy.

Tuberculosis is the most common cause of death in HIV-infected patients. Isoniazid is used as a first-line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co-infected patients is therefore critical. Plasma levels of isoniazid, acetyl-isoniazid, and isonicotinic acid from 63 patients co-infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed-effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz-based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3-fold and 2.3-fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz-based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl-isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid-related toxicity and treatment failure is presented.